Metabolic Control of Cancer 2021

CHAPTER THREE
Metabolic control of cancer

progression as novel targets
for therapy
Sarmistha Talukdara,b, Luni Emdada,b,c, Rajan Gognaa,b,
Swadesh K. Dasa,b,c, and Paul B. Fishera,b,c,*
a
Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine,
Richmond, VA, United States
b
VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond,
VA, United States
c
VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA,
United States
*Corresponding author: e-mail address: paul.fisher@vcuhealth.org
Contents
1. Introduction 104
1.1 Glucose metabolism 105
1.2 Lipid metabolism 110
1.3 Glutamine metabolism 114
1.4 Nucleic acid metabolism 118
1.5 One carbon metabolism 122
1.6 Oncometabolites 125
2. Metabolic heterogeneity between tumor types 126
3. Metabolic strategies engaged during tumorigenesis 130
4. Metabolic regulation of metastasis 131
4.1 Glucose metabolism in metastasis 131
4.2 Lipid metabolism in metastasis 134
4.3 Epigenetic regulation of metastatic metabolic rewiring 137
4.4 Regulation of EMT by oncogenic metabolism 138
4.5 Metabolism of circulating cancer cells 139
5. Tumor-microenvironment and metabolic crosstalk in cancer progression 140
5.1 Hypoxia and cancer cell metabolism 141
5.2 Metabolic coupling between tumor cells and stroma 142
5.3 Metabolic preconditioning of the metastatic niche 143
6. Overlap in metabolic signatures of cancer cells and stem cells 143
6.1 Metabolic strategies used by cancer cells and pluripotent stem cells 144
6.2 Metabolic regulation of chromatin and differentiation 145
6.3 Metabolic heterogeneity of cancer stem cells 145
Advances in Cancer Research, Volume 152 Copyright # 2021 Elsevier Inc. 103
ISSN 0065-230X All rights reserved.
https://doi.org/10.1016/bs.acr.2021.06.002
104 Sarmistha Talukdar et al.
7. Metabolism and cancer therapy 147

7.1 Chemotherapeutically targeting metastasis through metabolism 147
7.2 Ionizing radiation and metabolism 155
7.3 Targeting stromal cell metabolism for therapy 156
8. Conclusion 157
9. Future prospects 158
Acknowledgments 158
References 159
Abstract
Metabolism is an important part of tumorigenesis as well as progression. The various
cancer metabolism pathways, such as glucose metabolism and glutamine metabolism,
directly regulate the development and progression of cancer. The pathways by which
the cancer cells rewire their metabolism according to their needs, surrounding environ-
ment and host tissue conditions are an important area of study. The regulation of these
metabolic pathways is determined by various oncogenes, tumor suppressor genes, as
well as various constituent cells of the tumor microenvironment. Expanded studies on
metabolism will help identify efficient biomarkers for diagnosis and strategies for ther-
apeutic interventions and countering ways by which cancers may acquire resistance to
therapy.
1. Introduction
Metabolic reprogramming is considered a hallmark of cancer, and this
has been an area of extensive research for a long time (Hanahan & Weinberg,
2011; Phan, Yeung, & Lee, 2014; Ward & Thompson, 2012). Under con-
ditions of abundance of nutrients, oncogenic signaling pathways cause
upregulated nutrient acquisition and help the conversion of this assimilated
carbon into biomacromolecules such as lipids, proteins and nucleic acids to
support increased cell growth and proliferation (Boroughs & DeBerardinis,
2015). Research groups have consistently observed that glucose along with
glutamine metabolism are usually reprogrammed by mutations in MYC,
TP53, the Ras-related oncogenes, the LKB1-AMP kinase (AMPK) and
PI3 kinase (PI3K) signaling pathways, among others. This regulation of
oncogenic signaling and nutrient availability directly control cancer cell
metabolism (Boroughs & DeBerardinis, 2015). Cancer cells are capable of
optimizing nutrient utilization when resources are scarce to withstand the
harsh environment of solid tumors (Boroughs & DeBerardinis, 2015).
This metabolic flexibility has been observed in both cultured cells and
in vivo (Boroughs & DeBerardinis, 2015; Goodpaster & Sparks, 2017).
Metabolic control of cancer progression as novel targets 105
Emerging evidence suggests that cancer cells have much more complex
metabolic requirements than previously appreciated and that numerous
pathways are also involved in this process (Boroughs & DeBerardinis,
2015). These processes can be anabolic or catabolic in nature; catabolic pro-
cesses include glycolysis, and the citric acid cycle, which involves breaking
down of a molecule. Biosynthetic or anabolic pathways enable cancer cells
to synthesize the biomacromolecules required for the increased replicative cell
division and tumor growth (DeBerardinis & Chandel, 2016). Proteins, lipids,
and nucleic acids, are the three biomacromolecular classes frequently studied
in cancer metabolism and they comprise approximately 60%, 15%, and 5% of
the dry mass of mammalian cells, respectively (DeBerardinis & Chandel,
2016). Evidence indicates that biosynthesis as well as breakdown of all three
classes is under the control of the various signaling pathways that govern can-
cer cell growth and are activated in cancer. This leads to metabolic needs and
vulnerabilities which continue to evolve throughout cancer progression
(Faubert, Solmonson, & DeBerardinis, 2020). Tumors acquire dependence
on new pathways during later stages of cancer progression, particularly during
the metastasis and therapy resistance stages, which may differ starkly from early
stages of cancer (Fig. 1). The initial stages of tumorigenesis occur within the
metabolic constraints of the native tissue, however gradual accumulations of
somatically acquired mutations change tumor biology and cause metabolic lia-
bilities to evolve. In this review we discuss some of these pathways by which
metabolism controls cancer progression.
1.1 Glucose metabolism

Glucose metabolism is a critical processes that gets drastically changed during
the transition of normal to cancer cells (Annibaldi & Widmann, 2010), which
makes it an important target in therapy ( Jang, Kim, & Lee, 2013). Tumor
cells, utilize glucose for aerobic glycolysis over oxidative phosphorylation.
This increased aerobic glycolysis is considered as one of the hallmarks of cancer
(Annibaldi & Widmann, 2010; Hanahan & Weinberg, 2011; Vander Heiden,
Cantley, & Thompson, 2009), among other characteristics such as having
unlimited replicative potential, self-sufficiency in growth signals, resistance
to apoptosis, insensitivity to antigrowth signals, sustained angiogenesis, along
with host tissue invasion and spread by metastasis (Hanahan & Weinberg,
2011). A common view of cancer cell metabolism invokes a switch from glu-
cose oxidation in normal tissues toward anaerobic glycolysis and suppressed
oxidative phosphorylation in cancer (DeBerardinis & Chandel, 2016).
Popula on of Therapy resistant
subtype speciﬁc cells
metabolic proper es
Metabolic symbiosis with CAFs
Anoikis
Circula ng
Loca on speciﬁc
tumor cells
metabolic needs
with redox
homeostasis
Fig. 1 Interconnections between tumor metabolism with Hanahan and Weinberg’s Hallmarks of Cancer (Lewis & Abdel-Haleem, 2013).
Metabolic needs and vulnerabilities evolve throughout the process of cancer progression. Early stages of tumor growth require nutrient
uptake and biosynthesis, with additional subtype-selective metabolic needs emerging in locally invasive cancers. Tumors acquire depen-
dence on new pathways during later stages of cancer progression, particularly metastasis and therapy resistance. These include potentially
targetable liabilities such as dependence on mechanisms to resist oxidative stress and increased reliance on oxidative phosphorylation.
Adapted from Woolf, E. C., Syed, N., & Scheck, A. C. (2016). Tumor metabolism, the ketogenic diet and β-hydroxybutyrate: Novel approaches to
adjuvant brain tumor therapy. Frontiers in Molecular Neuroscience, 9, 122. doi: https://doi.org/10.3389/fnmol.2016.00122 and Faubert, B.,
Solmonson, A., & DeBerardinis, R. J. (2020). Metabolic reprogramming and cancer progression. Science, 368 (6487). doi: https://doi.org/
10.1126/science.aaw5473.
A
Glycolysis
Oxphos
Ac vated in cancer Inac vated in cancer
Glycolysis Oxphos
Glycolysis Oxphos
Fig. 2 Relationship between glycolysis and oxidative phosphorylation in cancer cells.

(A) Schema showing the most accepted view on the state of glucose metabolism in can-
cer cells. In cancer cells aerobic glycolysis is activated whereas oxidative phosphoryla-
tion is largely suppressed. (B) Some studies however show that in cancer cells both
glycolysis and oxidative phosphorylation pathways are activated.
Other researchers state that tumors seem to develop both glycolysis and glucose
oxidation pathways simultaneously relative to surrounding tissue (Fig. 2).
Glycolysis is an important catabolic process that breaks down one
molecule of glucose into two pyruvates with the production of two ATP
and two reduced nicotinamide adenine dinucleotide (NADH) molecules
(Fig. 3). Hypoxia is considered as the main instigator that drives tumor cells
to fuel glucose in a nonoxidative “glucose to lactate” pathway. However,
some studies have reported that the glycolytic switch is acquired by the can-
cer cells very early in carcinogenesis even before tumors experience hypoxia
(Annibaldi & Widmann, 2010; Vander Heiden et al., 2009; Zhou et al.,
2011). This leads to increased uptake of glucose and produces enough met-
abolic intermediates and energy that cancer cells need to sustain their rapid
proliferation. One of these intermediates, glucose 6-phosphate is utilized in
the biosynthesis of nucleic acid, through the pentose phosphate pathway, to
sustain rapid DNA replication. The generous production of pyruvate acti-
vates lipid synthesis that is necessary for the formation of membranes in
Fig. 3 (A) Glucose metabolism in cancer cells. Glycolysis is a catabolic process, regulated by several key enzymes as depicted. Additionally,
cancer cells show that the pyruvate generated can either be converted into lactate or used to drive the TCA cycle. The glycolytic flux in cancers
is tightly controlled (as shown) to meet the fast-proliferative needs. Several factors such as HIF, MYC and KRAS regulate this process. Other
metabolites such as citrate or ATP can also regulate this process by feedback regulation. (B) Regulation of cell death by glucose metabolism.
Presence of glucose, either high or low can contribute to the regulation of cell death. In conditions where the amount of glucose availability is
low, proapoptotic factors are activated and anti-apoptotic factors are inhibited. When the glucose availability is high, cell proliferation is
favored instead. Panel (A): From Yan, L., Raj, P., Yao, W., & Ying, H. (2019). Glucose metabolism in pancreatic cancer. Cancers (Basel), 11(10),
1460. doi: https://doi.org/10.3390/cancers11101460.
dividing tumor cells. In addition, lactic acid secretion by the proliferating

tumor cells causes acidification of the tumor microenvironment that tailors
a particular niche, which supports further tumor progression, along with
resistance to some anticancer drugs (Annibaldi & Widmann, 2010).
It has also been reported by various groups that oncogenes prevalent in
wide variety of human cancers can directly activate HIF-1 and other com-
ponents of glucose metabolism independently of hypoxia, such as Akt, also
known as the “Warburg kinase.” Akt can regulate the metabolic changes in
tumor cells to lead to a more aggressive state (Annibaldi & Widmann, 2010;
Robey & Hay, 2009). Akt creates a glycolytic switch under normoxia con-
ditions, without affecting the rate of oxidative phosphorylation, which
evolved possibly as an adaptation to low-oxygen flux along with the need
to produce metabolic intermediates required for rapid proliferation.
Another oncogene, K-Ras is reported by several groups to change the glu-
cose metabolism pathway through HIF-1α to offer cancer cells a selective
advantage (Annibaldi & Widmann, 2010; Bose & Le, 2018). Some of the
other reported oncogenes, such as PI3K, and VHL, also act through
HIF-1α (Annibaldi & Widmann, 2010; Bose & Le, 2018; Yeung, Pan, &
Lee, 2008), resulting in the expression of HIF-1α without the need for hyp-
oxic conditions.
Glycogenolysis, is the process by which glycogen is converted to glucose-
1-phosphate (G1P) and then to glucose-6-phosphate (G6P) to enter the gly-
colytic pathway, and this offers another energy source for tumors during the
conditions of nutrient deprivation (Bose & Le, 2018). Glycogen metabolism,
is upregulated in several cancer types including renal, breast, bladder, uterine,
ovarian, skin, and brain cancers. Some researchers have also shown that the
glycogen content of cancer cells is inversely proportional to the rate of repli-
cation (Bose & Le, 2018; Rousset, Zweibaum, & Fogh, 1981). Both glyco-
genolysis and glycogen synthesis enzymes are reported to be highly expressed
by tumor cells with HIF-1α dependence, including UGP2, PGM, GBE,
GYS1, and PPP1R3C (Bose & Le, 2018; Zois, Favaro, & Harris, 2014).
Supporting this finding it was observed that inhibition of glycogen synthase
kinase 2 (GSK2) activity resulted in decreased prostate tumor growth in vivo
(Bose & Le, 2018; Zhu et al., 2011). Glycogen metabolism is thus another
important target of therapy that supports cancer cells in conditions of poor
angiogenesis (Bose & Le, 2018; Ros & Schulze, 2012).
Glucose metabolism apart from regulating nucleotide synthesis and the
fatty acid pathway, can also influence nutrient availability, which directly
regulates cell death through death receptors, antiapoptotic Bcl-2 family
member Mcl-1, pro-apoptotic BH3-only proteins (Puma, Bim, Noxa and

Bad) and c-FLIP (Muñoz-Pinedo, El Mjiyad, & Ricci, 2012). Glucose dep-
rivation is reported to cause necrosis, caspase-8-mediated, but death recep-
tor independent, apoptosis (Caro-Maldonado et al., 2010; Muñoz-Pinedo
et al., 2012) or mitochondrial apoptosis mediated by Noxa, Puma, Bad or
Bim (Fig. 3) demonstrating the importance of this metabolic pathway in
cancer progression and therapy.
1.2 Lipid metabolism

Lipids, are an extremely diverse class of biomacromolecules, and they reg-
ulate three main roles in cells: (1) energy storage, mainly as triacylglycerol
esters and steryl esters, in lipid droplets (LDs) (Fernández, Gómez de
Cedrón, & Ramı́rez de Molina, 2020), (2) as structural components of
cellular membranes, and (3) functioning as metabolic signaling messengers
(Fernández, et al., 2020; van Meer, Voelker, & Feigenson, 2008; Wang,
Bai, Li, & Cui, 2020). The sterol regulatory element-binding proteins
(SREBPs) act as transcription factors which control the synthesis and uptake
of lipids, activated by upstream signaling networks and intracellular nutrient
status (Fernández et al., 2020; Peck & Schulze, 2019). Mutations in onco-
genes that support lipid metabolism reprogramming in cancer, along with
systemic lipid metabolic alterations associated with obesity, are critical risk
factors for cancer (Fig. 4). De novo lipogenesis comprised of fatty acids
and cholesterol biosynthesis, are the main contributors of lipid metabolism
in cancer (Fig. 4). Lipid metabolic reprograming is a hallmark of cancer and
this process regulates not only the tumor microenvironment but also the
cancer cell phenotype, thereby contributing to the occurrence and develop-
ment of tumors (Hao et al., 2019; Wang et al., 2020). In vitro studies,
preclinical, and clinical trials have shown the role of lipid metabolism in can-
cer initiation and progression (Fernández et al., 2020; Gómez de Cedrón &
Ramı́rez de Molina, 2020). Studies involving the suppression of lipid met-
abolic enzymes report tumor regression, inhibition of metastatic spread,
and/or sensitivity to drugs (Fernández et al., 2020). Lipids are in addition
a source of energy by means of β-FA oxidation (β-FAO), contributing to
the control of redox homeostasis, and acting as signaling molecules in cancer
proliferation, migration, invasion, transformation, tumor microenviron-
ment reshaping, and/or modulation of inflammation (Fernández et al.,
2020; Orita et al., 2007; Zaytseva et al., 2018). Cholesterol is one of the sem-
inal components of the cell membranes, regulating cell fluidity, stabilizing
Fig. 4 See figure legend on next page.
lipid rafts to transduce intracellular cell signaling pathways (Fernández et al.,

2020; Orita, Coulter, Tully, Kuhajda, & Gabrielson, 2008), and being precur-
sors of steroidal hormones (Alli, Pinn, Jaffee, McFadden, & Kuhajda, 2005;
Fernández et al., 2020).
Cancer cells utilize diet-derived fatty acids through LPL, CD36, FATPs,
and FABPpm. Glucose is converted into acetyl-CoA by glycolysis and on to
citrate through the TCA cycle in the mitochondria, which end up as carbon
sources for the growing acyl chains, while the pentose phosphate pathway
from glycolysis generates NADPH. This NADPH is linked with the fatty
acid synthesis machinery, and this machinery is different in cancer cells from
that observed in normal cells (Fig. 5) (Wang et al., 2020). In glioblastoma
patients, cancer stem cells have been observed to overexpress genes involved
in the mevalonate pathway, which is closely linked with lipid metabolism
(Peiris-Pages, Martinez-Outschoorn, Pestell, Sotgia, & Lisanti, 2016).
Fig. 4 (A) Main metabolic pathways related to lipid metabolism in cancer: Illustration of
pathways and genes implicated in de novo lipogenesis—fatty acids and cholesterol bio-
synthesis. ABCA1, ATP-binding cassette subfamily A member 1; ABCG1, ATP-binding
cassette subfamily G member 1; ABCG4, ATP-binding cassette subfamily G member
4; ABCG5, ATP-binding cassette subfamily G member 5; ABCG8, ATP-binding cassette
subfamily G member 8; ACAT, acetyl-CoA acetyltransferase; ACC, acetyl-CoA carboxylase;
ACLY, ATP citrate lyase; ACSL, acyl-CoA synthetase long chain; AGPAT, 1-acylglycerol-
3-phosphate O-acyltransferase; CD36, CD36 molecule; CPT1, carnitine palmitoyl
transferase; DGAT, diacylglycerol O-acyltransferase; FA, Fatty acids; FASN, fatty acid
synthase; GPAT, glycerol-3-phosphate acyltransferase; HDL, high-density lipoprotein;
HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS, 3-hydroxy-3-methylglutaryl-
CoA synthase; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LPIN,
Lipin; NR1H2, nuclear receptor subfamily 1 group H member 2; NR1H3, nuclear receptor
subfamily 1 group H member 3; PLIN, perilipin; PPARγ, peroxisome proliferator-activated
receptor γ; PTGS, prostaglandin-endoperoxide synthase; SCD1, stearoyl-CoA desaturase;
SREBP1, Sterol regulatory element binding transcription factor 1; SREBP2, sterol regulatory
element binding transcription factor 2; TCA, tricarboxylic acid cycle. (B) Relevance of lipid
metabolism alterations in cancer. Illustrated is the crucial role of (i) oncogenic mutations
supporting the lipid metabolism reprogramming in cancer, together with (ii) systemic
lipid metabolic alterations associated with obesity—as an environmental modifiable risk
factor. Precision interventions should include therapeutic clinical drugs targeting identi-
fied lipid metabolism molecular targets together with nutritional interventions—bioactive
compounds, diet-derived ingredients—considering the nutritional and metabolic status of
patients. T2DM, type 2 diabetes mellitus; IR, insulin resistance; TME, tumor microenviron-
ment; CAAs, cancer-associated adipocytes; FAO, fatty acid oxidation; FA, fatty acid. Panels
(A) and (B): From Fernández, L. P., Gómez de Cedrón, M., & Ramírez de Molina, A. (2020).
Alterations of lipid metabolism in cancer: Implications in prognosis and treatment.
Frontiers in Oncology, 10(2144). doi: https://doi.org/10.3389/fonc.2020.577420.
In addition, MYC can also regulate mevalonate metabolism (Wang et al.,

2017, 2020) further supporting the interplay between the two pathways
(Fig. 4) (Fernández et al., 2020). Tumor cells also utilize circulating free
FAs (FFAs) generated by lipolysis as an energy source for membrane biosyn-
thesis or various signaling processes (Wang et al., 2020). Involvement of
sphingolipid homeostasis has been reported in various solid tumors and hema-
tological malignancies (Lewis, Wallington-Beddoe, Powell, & Pitson, 2018;
Wang et al., 2020). Recent studies also show that protective role of
medium-chain acyl-CoA dehydrogenase in eliminating lipid molecules that
may cause lethal cell damage (Puca et al., 2021). These studies show the intri-
cate ways by which lipid metabolism is connected to and regulated by various
other metabolic pathways and how it contributes to the regulation of cancer
metabolism.
1.3 Glutamine metabolism

Glutamine is important for cell metabolism as it provides the cells with
reduced nitrogen for biosynthetic reactions, and a source of carbon to support
the tricarboxylic acid (TCA) cycle, and also helps in the production of gluta-
thione, nucleotides and lipids (Fig. 6) (Altman, Stine, & Dang, 2016; Chen &
Fig. 5 Lipid metabolism overview in normal and cancer cells. Cancer cells acquire
diet-derived FA through LPL, CD36, FATPs, and FABPpm. Glucose is converted into
acetyl-CoA by glycolysis and on to citrate through the TCA cycle in the mitochondria.
The citrate is transported to the cytoplasm and converted back to acetyl-CoA by citrate
lyase, which is used as the carbon source for the growing acyl chains. The pentose phos-
phate pathway from glycolysis generates NADPH. Cancer cells also develop effective de
novo FAS machinery with an increase in the activity of key lipogenic enzymes. The sur-
plus lipids (including excess FAs and cholesterol) in a cell exist in the form of neutral,
inert biomolecules in the core of LDs. ATGL catalyzes the initial step of lipolysis, conver-
ting TGs to DGs; HSL is primarily responsible for the hydrolysis of DGs to MGs, and MAGL
hydrolyzes MGs into FFA and glycerol. CPT1, as an outer mitochondrial membrane
enzyme, translocates FA across the mitochondrial membranes and then the degrada-
tion of long-chain FAs occurs in the mitochondria. Cholesterol homeostasis involves
the interplay between de novo synthesis (mevalonate pathway), uptake of dietary
cholesterol, and removal of excess cholesterol from peripheral tissues. 27-HC is the
metabolite substrate of cholesterol by CYP27A1 enzymes. SREBP-1 is activated through
the PI3K/Akt/mTOR pathway and the Ras/Raf/MEK/ERK signaling pathway. From
Wang, W., Bai, L., Li, W., & Cui, J. (2020). The lipid metabolic landscape of cancers and
new therapeutic perspectives. Frontiers in Oncology, 10, 605154. doi: https://doi.org/
10.3389/fonc.2020.605154.
Fig. 6 (A) Different uses of glutamine in cancer cells. Glutamine enters the cells through
transporters such as SLC1A5. Once inside the cell, glutamine can contribute to nucleo-
tide biosynthesis directly (through CAD, for example) or is converted to glutamate by
GLS. Moreover, it can also be exported outside of the cell for the import of leucine, a
coactivator of GDH. Then, glutamate can be converted to α-KG by GDH. Glutamate
can contribute to the synthesis of glutathione through the activity of different enzymes,
such as GCL. Amino acid synthesis is supported by the aminotransferases (such as GOT)
which converts glutamate to α-KG. Glutamine-derived α-KG can enter the TCA cycle to
produce energy for the cell or proceed backwards via the reductive carboxylation to
provide an alternative source of lipid synthesis. Moreover, α-KG is a co-substrate of
dioxygenase enzymes (such as JHMD and TED) in the regulation of histone and DNA
methylation. α-KG: α-ketoglutarate; CAD: carbamoyl-phosphate synthetase 2 aspartate
transcarbamylase, and dihydroorotase; CTP: CTP synthetase; GCL: glutamate-cysteine
ligase; GLS: glutaminase; GDH: glutamate dehydrogenase; GOT: glutamate-oxaloacetate
transaminase; JHMD: Jumonji C histone demethylases; TED: TET DNA demethylases.
(B) Glutamine metabolism and potent targets for cancer therapy. After transporting into
cytosol by LAT1 (l-type amino acid transporters 1), ASCT2 (system ASC amino acid trans-
porters 2) and other transporters, glutamine is catalyzed by glutaminase and converts to
glutamate and ammonia. It then provides macromolecular material for ammonia acid
and lipid syntheses. Glutamine is also used to exchange EAAs, which could activate
mTOR and promote cell growth. Glutamate is also used to exchange extracellular
cysteine for GSH production. GLS is a key enzyme for glutamine metabolism, which
can be inhibited by several inhibitors including 968, BPTES and CB-839, accompanying
with other inhibitors of glutamine metabolism are shown in red circle. GLS, glutaminase;
GDH, glutamate dehydrogenase; TA, transaminase; OAA, oxaloacetate; BCH, 2-
aminobicyclo-(2,2,1)-heptane-2-carboxylic acid; GPNA, γ-l-glutamylp-nitroanilide; EGCG,
epigallocatechin gallate; EAAs, essential ammonia acids; mTOR, mammalian target of
rapamycin; BPTES, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3; 968,
5-(3-bromo-4-(dimethylamino) phenyl)-2,2-dimethyl-2,3,5,6-tetrahydrobenzo[a]phe-
nanthridin-4(1H)-one; CB-839, N-(5-(4-(6-((2-(3-(trifluoromethoxy)phenyl)acetyl)amino)-
3-pyridazinyl)butyl)-1,3,4-thiadiazol-2-yl)-2-pyridineacetamide. ┴, inhibiting effect; bold
black arrow, main metabolic pathway and transportation of glutamine; black arrow,
metabolic pathways of glutamine and glucose. (C) Glutamine consumption is increased
in most tumors. During tumorigenesis, glucose derived lactate is increased, and at the
same time, contribution of glucose to TCA is decreased. Accompanied with glucose
metabolism change, glutamine metabolism is up-regulated to compensate energy
and macromolecular for cell proliferation and growth. p53 is mutated, while MYC is
overexpressed, which promotes glutamine metabolism by upregulating GLS1 activity
during tumorigenesis. GLS1 is highly expressed in many tumors and promotes tumor
proliferation. In contrast, GLS2 expression is reduced in some tumors. GLS, glutaminase;
TCA, tricarboxylic acid cycle. Bold arrow, increased glutamine metabolism, decreased
glucose metabolism and mutated MYC; dashed line, tumorigenesis procedure.
Panel (A): From Loo, J. M., Scherl, A., Nguyen, A., Man, F. Y., Weinberg, E., Zeng, Z., et al.
(2015). Extracellular metabolic energetics can promote cancer progression. Cell, 160(3),
393–406. doi: https://doi.org/10.1016/j.cell.2014.12.018. Epub 2015 Jan 15. Panels (B) and
(C): From Chen, L., & Cui, H. (2015). Targeting glutamine induces apoptosis: A cancer ther-
apy approach. International Journal of Molecular Sciences, 16(9), 22830–22855. doi:
https://doi.org/10.3390/ijms160922830.
Cui, 2015; Cluntun, Lukey, Cerione, & Locasale, 2017; DeBerardinis &
Chandel, 2016; Jiang et al., 2016; Nguyen & Durán, 2018; Pavlova &
Thompson, 2016). A common metabolic characteristic of many cancer cells
is an increased dependency on exogenous supply of glutamine (Fig. 6) which
is also known as glutamine addiction (Li et al., 2015). It has been reported that
the absence of exogenous glutamine caused cell death in several cancer cell
types (Cluntun et al., 2017; Eagle, 1955). Glutamine is one of the most prev-
alent nonessential amino acids present in the bloodstream and it supports
almost every biosynthetic pathway required for cell proliferation, such as
purine and pyrimidine synthesis along with protein and glutathione biosyn-
thesis (Cluntun et al., 2017; Jain et al., 2012). Addiction of cancer cells to
glutamine can result from genetic alterations that regulate the oxidative mito-
chondrial function (Cluntun et al., 2017; Hosios et al., 2016). HIF1-α and
mutated IDH-1 are some of the proteins that regulate glutamine addiction
(Cluntun et al., 2017). The need for glutamine also changes after cancer
cells transition from monolayer culture to anchorage-independent culture
(Cluntun et al., 2017; Jiang et al., 2016). Some research groups report that
glutamine was not required for tumorigenesis in vivo in specific mouse
models (Cluntun et al., 2017; Davidson et al., 2016). However, the majority
of studies indicate that dependency on glutamine exists in many in vivo
settings (Chakrabarti et al., 2015; Cluntun et al., 2017; Fendt, Bell,
Keibler, Davidson, et al., 2013; Gross et al., 2014; Reid et al., 2016; Shroff
et al., 2015; Son et al., 2013; Xiang et al., 2015). Tumors exhibit a variety
of metabolic phenotypes depending on the tissue of origin, the cancer sub-
type, as well as the tumor microenvironment. Even among tumors that arise
in a specific organ, heterogeneity may exist in the form of different cancer sub-
types with distinct patterns of glutamine metabolism. For example, luminal
breast cancers frequently exhibit high GLUL and low GLS expression, while
basal breast cancers show an opposite relationship (Cluntun et al., 2017; Kung,
Marks, & Chi, 2011) with basal cells highly sensitive to glutamine withdrawal
and to inhibition of GLS, both in cell culture and when grown as xenograft
tumors in vivo (Cluntun et al., 2017; Gross et al., 2014; Kung et al., 2011).
Metabolic heterogeneity is also reported among the different regions of
the same tumor. For example, highly perfused regions of NSCLC tumors
oxidize various nutrients to drive the TCA cycle, whereas less perfused
regions primarily utilize glucose-derived carbon only (Cluntun et al.,
2017; Hensley et al., 2016). Thus, some tissue tumors (such as basal breast
cancer) are more dependent on glutamine, as compared to NSCLC, which
are more dependent on pyruvate to maintain TCA cycle flux (Cluntun
et al., 2017).
1.4 Nucleic acid metabolism

The nuclei of cells contain important genetic information, and this informa-
tion resides in specific genes or DNA molecules coded by sequences of
nucleotide pairs (Goldthwait, 1960). This information is capable of deter-
mining the sequence of amino acids required for production of a specific
protein and is under the regulation of particular gene or DNA molecule.
Altered amino acid sequence in the protein possibly results from altered
nucleotide sequence(s) in the DNA molecule. The steps which process
the transfer of information from the DNA to the protein involve the syn-
thesis of specific RNA molecules present in the ribonucleoprotein granules
of the endoplasmic reticulum (Goldthwait, 1960). This is the major protein
synthesis system, where the specific RNA codes act as a template, according
to which the amino acids are aligned in a sequence unique for the particular
protein. Following peptide bond formation, the protein or enzyme mole-
cule is released. The processes of carcinogenesis may be viewed as alterations
or corruption of the transferred information (Goldthwait, 1960) in this
system. A critical component of this system based on RNA and DNA tem-
plate is the synthesis of ribonucleotides and deoxyribonucleotides required
for the formation of the information system.
Ribonucleotides (NTP) and deoxyribonucleotides (dNTP) form the
end products of purine and pyrimidine synthesis (Peters, 1994) by using both
the de novo and the salvage pathways (Fig. 7) (Kimura & Huang, 2016). They
form the direct substrates for RNA and DNA synthesis (Peters, 1994).
Nucleotide homeostasis in the cell are the consequence of a dynamic equi-
librium of synthesis and consumption (Peters, 1994). Along with their vital
role in RNA synthesis, ribonucleotides are also important for a number of
other functions in the cell, such as energy source supply (ATP), nucleotide
sugar synthesis (UTP, CTP and GTP), lipid biosynthesis (CTP), signal trans-
duction (ATP, GTP as part of the GTP binding protein, cyclic nucleotides
such as cAMP and cGMP), protein elongation, tubulin-binding and ras-
oncogene (all GTP), phosphate donors for kinase catalyzed reactions (mostly
ATP, but other nucleotides can also act as a phosphate donor), allosteric acti-
vators and feedback regulators of several synthetic pathways, co-enzyme in
several synthetic reactions such folyl-polyglutamate synthetase and phos-
phoribosyl pyrophosphate (PRPP) synthetase (Peters, 1994). dNTPs not only
act as the substrate for DNA synthesis, but they also play a critical role in DNA
repair and as feedback regulators of a number of enzymes. For example, dTTP
is an inhibitor of dCMP deaminase (Marx & Alian, 2015; Peters, 1994), and of
Fig. 7 Schemas for purine (A) and pyrimidine (B)-related metabolic pathways. (C) Cytosolic
DNA sensing orchestrates tumor immunity during radiotherapy. Exposure to radiation
results in the generation of DNA fragments which attract phagocytosing cells. This phago-
cytosis leads to release of the DNA fragments from the radiated cells into myeloid cells. This
triggers a signaling cascade that leads to the production of Interferon (IFN). Radiation can
also regulate the behavior of T cells and macrophages. Panels (A) and (B): From Kimura, K. &
Huang, R. C. (2016). Tetra-o-methyl nordihydroguaiaretic acid broadly suppresses cancer
metabolism and synergistically induces strong anticancer activity in combination with
etoposide, rapamycin and ucn-01. PLoS One, 11 (2), e0148685. doi: https://doi.org/10.1371/
journal.pone.0148685.
thymidine kinase (Birringer et al., 2005; Peters, 1994); while dATP is a potent
feedback inhibitor of ribonucleotide reductase (Ando et al., 2016; Peters,
1994), to name a few (Peters, 1994).
Cancer cells are notably dependent on a sufficient supply of nucleotides
and other macromolecules to grow and proliferate, due to their higher pro-
liferative rates (Villa, Ali, Sahu, & Ben-Sahra, 2019). To meet these high
metabolic demands, cancer cells must stimulate de novo nucleotide synthesis
to obtain adequate nucleotide supply to support nucleic acid and protein
synthesis along with energy preservation, signaling activity, glycosylation
mechanisms, and cytoskeletal functions (Villa et al., 2019). Oncogenes
and tumor suppressors are critical regulators of de novo nucleotide synthesis
pathways that contribute to the maintenance of homeostasis and the prolif-
eration of cancer cells. Inactivation of tumor suppressors such as TP53 and
LKB1 and hyperactivation of the mTOR pathway and of oncogenes such as
MYC, RAS, and AKT have been shown to fuel nucleotide synthesis in
tumor cells (Iurlaro, Leon-Annicchiarico, & Munoz-Pinedo, 2014; Villa
et al., 2019). The importance of oncogenes and tumor suppressors in the
short-term and long-term regulation of de novo nucleotide synthesis in tumor
cells is described in Table 1 (Villa et al., 2019). mTOR and MYC play a
global regulatory role in this process in cancer (Villa et al., 2019).
Nucleic acids are reported to perform another role in cancer, known as
nucleic acid sensing. Nucleic acid (NA)-sensing is an important component
of innate immunity where extranuclear DNA or extracellular RNA act as
damage-associated molecular patterns (DAMPs) signals (Fig. 7) (Deng,
Liang, Fu, Weichselbaum, & Fu, 2016; Desmet & Ishii, 2012; Iurescia,
Fioretti, & Rinaldi, 2018). Cells have two main cytosolic NA-sensing
pathways: the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon
genes (STING) and the RIG-I-like receptors (RLRs)-MAVS pathways,
which are responsible for cytosolic DNA and RNA sensing, respectively
(Chen, Uthaya Kumar, et al., 2016; Iurescia et al., 2018; Wu & Chen,
2014). NAs released by dying cancer cells can be sensed as DAMP danger
signals by PRRs present on CD8α dendritic cells (DCs) in the tumor micro-
environment (TME), which results in the activation of cGAS-STING and/or
RIG-I/MDA5 signaling pathways. This subsequently activates DCs in an
autocrine or paracrine manner, resulting in their migration to tumor-
draining lymph nodes, where DCs cross-prime naı̈ve CD8+ T lymphocytes
(Duewell et al., 2014; Iurescia et al., 2018; Klarquist et al., 2014; Woo et al.,
2014). Global occurrence of NA sensor proteins among various cancer types
suggests that these signaling mechanisms are integral to the biology of cancer
(Iurescia et al., 2018).
Table 1 Oncogenes and tumor suppressor genes involved in the short-term and
long-term regulation of de novo nucleotide synthesis in tumor cells.
Nature of the Description of the molecular
regulation Regulator(s) mechanism(s) References
Short-term RAS/ERK ERK directly phosphorylates Graves et al. (2000)
CAD on T456 and stimulates
CAD activity
PI3K/Akt/ mTORC1, through Ben-Sahra, Howell,
mTORC1 S6K1-mediated Asara, and Manning
phosphorylation of CAD on (2013); Robitaille
S1859, enhances flux through et al. (2013)
pyrimidine synthesis
Akt mediated-phosphorylation Saha et al. (2014)
of TKT on Thr382 enhances
PRPP availability for
nucleotide synthesis
Akt phosphorylates NADK on Hoxhaj et al. (2019)
S44/S46 to stimulate the
production of NADP(H), an
essential cofactor for
nucleotide synthesis
SIRT3 Inactivation of SIRT3 Gonzalez Herrera
promotes et al. (2018)
glutamine-dependent de novo
nucleotide synthesis in part
through hyperactivation of
mTORC1 signaling
PKM1 PKM1 expression impairs Lunt et al. (2015)
nucleotide production and the
ability to synthesize DNA and
progress through the cell cycle
Long-term K-RAS Oncogenic K-RAS stimulates Gaglio et al. (2011);
nucleotide synthesis through Santana-Codina et al.
regulation of RPIA expression (2018)
by c-MYC
MYC- During MYC-driven Cunningham,
eIF4E tumorigenesis, eIF4E controls Moreno, Lodi,
PRPS2 mRNA translation Ronen, and
through a cis-acting regulatory Ruggero (2014)
element and increases
nucleotide synthesis.
Continued
Table 1 Oncogenes and tumor suppressor genes involved in the short-term and
long-term regulation of de novo nucleotide synthesis in tumor cells.—cont’d
Nature of the Description of the molecular
regulation Regulator(s) mechanism(s) References
mTORC1 mTORC1 signaling, through Ben-Sahra et al.
activation of ATF4, stimulates (2013)
the expression of MTHFD2
required for one carbon formyl
unit incorporation into the
purine ring
PTEN Loss of PTEN stimulates de Mathur et al. (2017)
novo pyrimidine synthesis
through activation of
mTORC1 signaling
p53 Mutant p53 enhances the Kollareddy et al.
expression of nucleotide (2015)
metabolism genes
YAP1 YAP1 fuels de novo nucleotide Cox et al. (2016)
synthesis via the stimulation of
glutamine synthetase
expression (GLUL)
YAP1 fuels de novo nucleotide Cox et al. (2018)
synthesis via the stimulation of
glucose transporter 1
expression (GLUT1)
K-RAS and Simultaneous activation of Kim et al. (2017)
LKB1 KRAS and loss of LKB1
stimulates de novo pyrimidine
synthesis by elevating the
expression of carbamoyl
phosphate synthetase 1 (CPS1)
From Villa, E., Ali, E. S., Sahu, U., & Ben-Sahra, I. (2019). Cancer cells tune the signaling pathways to
empower de novo synthesis of nucleotides. Cancers (Basel), 11(5), 688. doi: https://doi.org/10.3390/
cancers11050688.
1.5 One carbon metabolism

One-carbon metabolism which regulates folate and methionine cycles, inte-
grates glucose, amino acids, and vitamins (Yu et al., 2019). In addition it also
supports the synthesis of nucleotides, lipids, and proteins; the maintenance of
redox balance; and the substrates for methylation reactions (Locasale, 2013;
Yu et al., 2019). The carbon units that fuel one-carbon metabolism are
obtained from specific amino acids, such as serine, glycine, and threonine,
or it can be synthesized de novo from glucose such as in the serine synthesis
pathway (SSP) (Locasale, 2013; Tsun & Possemato, 2015; Yu et al., 2019)
(Fig. 8).
In the one-carbon metabolic pathway, serine is converted into glycine in
the cytosol and mitochondrial matrix by serine hydroxymethyl transferase 1
and 2 (SHMT1 and 2), respectively (Martinez-Reyes & Chandel, 2014).
Covalent linkage of tetrahydrofolate (THF), derived from folic acid to a
methylene group (CH2) to form 5,10-methylene-tetrahydrofolate (5,10-
CH2-THF) is important in this process. Methylenetetrahydrofolate dehy-
drogenase (MTHFD1 and 2, respectively) present in the cytosolic and
mitochondria, both utilize 5,10-CH2-THF and NADP + as substrates to
produce 5,10-methenyl-tetrahydrofolate (5,10-CH]THF) and NADPH
(Martinez-Reyes & Chandel, 2014). The 5,10-CH]THF thus generated
is next converted into 10-formyl-THF, which is used for purine synthesis.
Thus, serine catabolism through one-carbon metabolism regulates can-
cer cell proliferation (Labuschagne, van den Broek, Mackay, Vousden, &
Maddocks, 2014; Martinez-Reyes & Chandel, 2014). Several studies have also
highlighted the role of serine in tumorigenesis. Serine is a non-essential amino
acid that can be either taken up by the cell or synthesized de novo from glyco-
lytic intermediates through the serine synthesis pathway (SSP) (Fig. 8) (Yang &
Vousden, 2016). Serine apart from feeding the one-carbon cycle also regulates
methylation reactions, antioxidant activity (Allen & Moskowitz, 1978; Davis
et al., 2004; Rowe, Sauer, Fahey, Craig, & McCairns, 1985; Yang & Vousden,
2016). Cells can access one-carbon groups from several other sources, includ-
ing glycine, choline, betaine, sarcosine, histidine and the generation of formate
from the catabolism of tryptophan (Brosnan, MacMillan, Stevens, & Brosnan,
2015; Tibbetts & Appling, 2010; Yang & Vousden, 2016). Serine-derived
one-carbon units are used for the de novo synthesis of adenosine, guanosine
and thymidylate, and for the re-methylation of homocysteine to support the
methionine cycle, as well as support the folate cycle (Yang & Vousden, 2016).
Even though one-carbon metabolism enzymes are present in both the
mitochondria and cytosol, most cells generate formate in the mitochondria
for cytosolic nucleotide synthesis. This directionality can also help in the
delivery of mitochondrial NADH, NADPH and ATP. Serine catabolism
is crucial for the maintenance of redox balance during hypoxia (Fig. 8)
(Martinez-Reyes & Chandel, 2014). In some cases the cancer cells highly
express SSP enzymes, and their survival is dependent on the sustained
Fig. 8 (A) Cytosolic and mitochondrial compartmentalization of one-carbon metabo-

lism. Serine and glycine contribute to one-carbon metabolism in largely parallel cyto-
plasmic and mitochondrial pathways. Serine hydroxymethyltransferate (SHMT1/2)
catalyzes the contribution of the serine beta carbon into the one carbon pool by pro-
duction of 5,10-methyl tetrahydrofolate (MeTHF). Cytoplasmic 5,10-MeTHF can then
contribute to dTMP synthesis or to most major methylation reactions of the cell via pro-
duction of S-adenosyl methionine. In the mitochondria, glycine can be further cleaved
to form another molecule of 5,10-MeTHF while in the cytoplasm, glycine instead can
contribute en masse to purine biosynthesis. One-carbon units are managed by the
methylenetetrahydrofolate dehydrogenases (MTHFD1/2), which can produce appropriate
(Continued)
expression of these enzymes, even under serine-fed conditions. (Yang &

Vousden, 2016). Cancer cells with lower expression of SSP enzymes tend
to depend on exogenous serine supply for optimal growth. The switch to
de novo serine synthesis under serine-starved conditions leads to increased oxi-
dative stress, which can affect the survival of these cells (Yang & Vousden,
2016). Several oncogenes and tumor suppressor genes, which regulate the
serine synthesis and one-carbon cycle enzymes, are also known regulators
of malignant development and progression (Yang & Vousden, 2016).
1.6 Oncometabolites
The term oncometabolites is used to designate the intermediate products of
metabolism that accumulate abnormally in cancer cells upstream or down-
stream of metabolic defects, often because of either loss-of-function or
gain-of-function mutations of the involved enzyme genes (Fig. 9). These
mutations lead to the accumulation of the endogenous oncometabolites,
which then drive crucial epigenetic and signaling changes regulating the pro-
gression of cancer cells (Collins, Patel, Putnam, Kapur, & Rakheja, 2017;
Mishra & Ambs, 2015; Rinaldi, Rossi, & Fendt, 2018). These intermediates
of metabolism are also clinically known as biomarkers of specific congenital
disorders of metabolism. D-2-Hydroxyglutarate, L-2-hydroxyglutarate, succi-
nate, and fumarate are the oncometabolites that are recognized presently
(Collins et al., 2017). These oncometabolites are structurally similar and share
metabolic proximity in the TCA cycle, and thus they also promote cancer cell
progression through similar mechanisms (Collins et al., 2017). Oncometabolite-
associated cancers can be diagnosed and studied through development and
validation of sensitive and specific assays that measure oncometabolites and
their downstream effectors (Mishra & Ambs, 2015). These biomarker-based
Fig. 8—Cont’d THF derivatives for nucleotide biosynthesis in the cytoplasm or for the
production of NADPH in either compartment. Serine and glycine are thought to move
across the inner mitochondrial membrane (IMM) via unknown transporters, while THF
derivatives and NADPH are not thought to translocate between these two compart-
ments. Green text denotes the fate of serine derived nitrogen, gray boxes indicate major
endpoint metabolites produced from serine. Key enzymes are shown in light blue.
(B) Serine and glycine can be transported into cells via neutral amino acid transporters
or synthesized de novo from glycolysis metabolites. 3PG, phosphoglycerate; 3PHP, phos-
phohydroxypyruvate; 3PS, 3-phosphoserine; PEP, phosphoenolpyruvate. Catabolism of
serine generated by this process regulates the redox balance in hypoxic cells. Panel
(A): From Tsun, Z. Y., & Possemato, R. (2015). Amino acid management in cancer.
Seminars in Cell & Developmental Biology, 43, 22–32. doi: https://doi.org/10.1016/j.semcdb.
2015.08.002. Epub 2015 Aug 12.
Fig. 9 Schema showing the oncometabolites generated by the TCA cycle. TCA cycle
produces several oncometabolites such as D-2-hydroxyglutarate, L-2-hydroxyglutarate,
succinate, and fumarate. These metabolic products regulate key stages of cancer pro-
gression such as EMT, redox signaling, nucleotide biosynthesis.
assays can be used as screening tools and for follow-up to measure response
to treatment, as well as to detect minimal residual disease and recurrence
(Collins et al., 2017; Mishra & Ambs, 2015). In addition, the genetic alter-
ations that lead to high levels of these metabolites, as well as the downstream
signaling pathways driven by them, can serve as attractive targets for ther-
apeutic interventions (Collins et al., 2017).
2. Metabolic heterogeneity between tumor types

The application of advanced technologies including metabolomics,
metabolic flux analysis, and functional genomics support the conclusion
that cancer cells and tumors have heterogeneous metabolic references and
dependencies (Kim & DeBerardinis, 2019). Metabolic phenotypes in
tumors are not only heterogeneous but also display plasticity, as they result
from the combined effects of many different factors. These factors are intrin-
sic to the cancer cell (e.g., cell lineage, differentiation state, and somatically
acquired mutations) while others are extrinsic in nature (e.g., nutrient milieu
and interactions with extracellular matrix and stromal cells) (Kim &
DeBerardinis, 2019). Convergent metabolic phenotypes arise downstream
of diverse regulatory influences (Kim & DeBerardinis, 2019). Such conver-
gent properties are reported in various cancer models and comprise of core
pathways such as those that allow cells to produce energy, build macromol-
ecules, and maintain redox balance. In spite of these convergences, divergent
metabolic phenotypes occur in distinct molecular subsets of cancer and con-
tribute to metabolic heterogeneity (Kim & DeBerardinis, 2019).
Extensive studies of cancer genetics and metabolism over the past two
decades highlight the significance of mutations in oncogenes and tumor sup-
pressors in the stimulation of cell-autonomous metabolic reprogramming
(Kim & DeBerardinis, 2019; Lunt & Fendt, 2018). Different mutations aris-
ing in the same cell tissue contribute to metabolic heterogeneity, as pointed
out by the divergent metabolic effects reported for these specific mutations
(Kim & DeBerardinis, 2019). Cell and tissue of origin can also contribute to
metabolic heterogeneity. Different tissues express different native metabolic
programs, which are retained in tumors originating in that tissue. Thus,
tumors arising in different tissues can exhibit divergent metabolic phenotypes
even if they contain the same oncogenic driver. Subsequently metabolic
intermediates which serve as cofactors and substrates for epigenetic changes,
can also contribute to heterogeneity. Epigenetic regulation of gene expres-
sion can also lead to metabolic heterogeneity as several metabolic enzymes
and nutrient transporters are regulated by epigenetic modifications of
histones (acetylation and methylation) and DNA (methylation) (Kim &
DeBerardinis, 2019; Lunt & Fendt, 2018). Equally, these epigenetic mod-
ifications also respond to the metabolic state of the cell (Figs. 10 and 11)
(Pascual, Dominguez, & Benitah, 2018) adding to the complexity of the het-
erogeneity. For example, the expression of SAM and SAH regulate DNA
and histone methyltransferases, while acetyl-CoA, the ratio of acetyl-CoA
to free CoA, and NAD levels can regulate histone acetylation (Kim &
DeBerardinis, 2019). The TCA cycle intermediate α-KG affects demethyl-
ation of histones and DNA by acting as a co-substrate for JHDM histone
demethylases and TET-family methylcytosine dioxygenases, respectively.
The oncometabolites fumarate, succinate, and 2-HG are dicarboxylates that
compete with α-KG, interfering with TET/JHDM function (Kim &
DeBerardinis, 2019; Lunt & Fendt, 2018) thus painting a very complex
and fluid picture of metabolic heterogeneity in tumors.
Fig. 10 Cancer metabolic plasticity contributes to metastatic disease. (A) Genetic mutations and epigenetic alterations in combination establish
unique populations of tumor-initiating cells (TICs). Only certain TICs take advantage of the surrounding cells that constitute the tumor micro-
environment (TME), such as vascular cells, cancer-associated fibroblasts (CAFs) and adipocytes, as well as their systemic environment, to
exchange and hijack metabolites (shown in green) that support TIC survival. TICs hijack metabolites while egressing out of the primary lesion,
thereby becoming metastasis-initiating cells (MICs). (B) As metastatic cells reach different distant organs via the vasculature, they adopt unique
metabolic states and engage in further metabolic crosstalk with the (C) metastatic niches that form, for example, in the bone, lungs, liver and
brain, ultimately supporting their survival. Tumor cells also secrete metastasis-promoting exosomes (yellow) that contain various proteins and
RNAs that contribute to establish distant pro-metastatic niches. From Pascual, G., Dominguez, D., & Benitah, S. A. (2018). The contributions of cancer
cell metabolism to metastasis. Disease Models & Mechanisms, 11(8), dmm032920. doi: https://doi.org/10.1242/dmm.032920.
Fig. 11 Epigenetic factors integrate metabolic cues that boost metastatic transcriptional programs in cancer cells. Yellow and red circles
represent diet-derived metabolites that are utilized by several epigenetic factors in active chromatin niches to post-translationally modify
histones and to methylate [blue circles are methyl groups (Me)] and hydroxymethylate [green circles are hydroxymethyl groups (hMe)] DNA.
The metabolic status of a cell influences chromatin configuration, via histone tail modifications, to generate transcriptionally restrictive or
permissive chromatin. A cell’s metabolic status can also influence DNA methylation patterns to regulate gene transcription. This interaction
between the cell metabolism and its epigenome can result in unique gene expression signatures that can contribute to the colonization of
distant organs and tissues by cancer cells. From Pascual, G., Dominguez, D., & Benitah, S. A. (2018). The contributions of cancer cell metabolism to
metastasis. Disease Models & Mechanisms, 11(8), dmm032920. doi: https://doi.org/10.1242/dmm.032920.
3. Metabolic strategies engaged during tumorigenesis

Tumor initiation is dependent on the reprogramming of cellular
metabolism resulting from both a direct and an indirect consequence of
oncogenic mutations (Dang, 2012). Apart from metabolic changes caused
by oncogenes, metabolic processes generate oxygen radicals, which contrib-
ute to oncogenic mutations (Dang, 2012). These activated oncogenes and
inactivated tumor suppressors in turn alter metabolism and induce aerobic
glycolysis. Aerobic glycolysis or the Warburg effect links the high rate of
glucose fermentation to cancer. Along with glutamine, glucose via glycolysis
provides the carbon skeletons, while NADPH, and ATP aid in the gener-
ation of new cancer cells. These substrates/signaling molecules react to hyp-
oxia further rewiring the metabolic pathways required for cell growth and
survival (Dang, 2012). Receipt of these signals allow pluripotency signaling
(Marsboom et al., 2016) as well as neoplastic growth in three-dimensional
multicellular masses, while local low nutrient and oxygen levels trigger the
growth of new blood vessels into the neoplasm (Dang, 2012; Marsboom
et al., 2016). The imperfect neovasculature in the tumor bed is poorly
formed and inefficient, but necessary in contributing and maintaining nutri-
ents and reducing hypoxic stress in the microenvironment (Bertout, Patel, &
Simon, 2008; Carmeliet et al., 1998; Dang, 2012; Semenza, 2012). In this
process, cancer cells and stromal cells collaborate to collectively recycle and
maximize the use of nutrients (Dang, 2012; Sonveaux et al., 2008), contrib-
uting to hypoxic adaptation that is critical for survival and progression of a
tumor. Increased expression of HIF proteins are pro-oncogenic, however,
carboxylic acids can also affect dioxygenases that are involved in epigenetic
modulation. Thus, the TCA cycle-mediated regulation of tumorigenesis are
multifaceted, complex and interdependent. Mutations in IDH also highlight
the importance of mutant metabolic enzymes in tumorigenesis (Dang, 2012;
Parsons et al., 2008; Yan et al., 2009). Mutations in metabolic enzymes
“hardwire: metabolic process to tumorigenesis, supported by mutations acti-
vating oncogenes or inactivating tumor suppressor genes to “softwire” met-
abolic regulation though cancer genes such as Myc, Ras, VHL and HIF-1
(Dang, 2012). In addition, disproportionate caloric intake is associated with
an increased risk for cancer, while caloric restrictions may have protective
effects, possibly though mitophagy, thereby reducing oxidative stress
(Dang, 2012).
4. Metabolic regulation of metastasis

Metastatic colonization of distant organs by cancer cells is a predictor of
poor prognosis in patients (Elia et al., 2017; Elia, Doglioni, & Fendt, 2018).
This denotes the importance of studying and targeting the mechanisms that
regulate the different steps of the metastatic cascade. Several metabolic path-
ways are reprogrammed in cancer cells to help in transition through the met-
astatic cascade, thereby aiding in the formation of secondary tumors in distant
organs (Elia et al., 2018). Indeed, metabolic reprogramming is a critical part of
the signaling pathways required for initial cancer invasion (intravasation).
In addition, circulating cancer cells depend on enhanced antioxidant defenses,
and cancer cells colonizing a distant organ require increased ATP production
suggesting the interplay of metabolism in the regulation of metastasis.
Furthermore, the local environment of the metastatic niche also regulates
the metabolic pathways that allow the secondary tumors to survive and grow.
In these contexts, metabolic reprogramming supports metastasis by regulating
several interlinked signaling pathways (Fig. 12) (Elia et al., 2018). Here we
describe some of these mechanisms of metastatic metabolic reprogramming.
4.1 Glucose metabolism in metastasis

The enzymes hexokinase (HK) 2 and pyruvate kinase (PK) M2 are crucial
for the initiation and end of glycolysis. HK2 and PKM2 irreversibly convert
glucose to glucose-6-phosphatase and phosphoenolpyruvate to pyruvate,
respectively. These enzymes are present in many fetal or embryonic and
proliferative (including cancer) tissues, although other isoforms of these
enzymes are mostly present in differentiated tissues (Elia et al., 2018; Elia,
Schmieder, Christen, & Fendt, 2016). The conversion mediated by HK
is the first rate-limiting step of glycolysis, whereas the PK based reaction
connects glycolysis to lactic acid and amino acid metabolism (Elia et al.,
2018; Lunt et al., 2015; Lunt & Vander Heiden, 2011). The influence of
HK2 and PKM2 on metastasis formation is very important (Botzer et al.,
2016). The presence of these enzymes is correlated with motility and
invasive capacity in cancer cells of different origin (Anderson, Marayati,
Moffitt, & Yeh, 2016; Liu et al., 2015; Lu et al., 2016; Sun et al., 2015;
Yu et al., 2015; Zhou, Choi, et al., 2012). Inhibition HK2 or PKM2 results
in reduced lactate production and glycolysis (Anderson et al., 2016; Elia
et al., 2018; Zhou, Choi, et al., 2012). These metabolic changes also regulate
Fig. 12 See figure legend on opposite page.
cancer cell motility and invasion, as glycolysis generates the metabolic

by-product methylglyoxal, which is reported to activate yes associated
protein (YAP) signaling in breast cancer cells (Elia et al., 2018; Nokin
et al., 2016), thereby contributing to EMT (Elia et al., 2018; Lei et al.,
2008; Overholtzer et al., 2006). In addition, lactate promotes breast cancer
progression by supporting chemoattraction, which aids cancer cell migration
(Bonuccelli, Tsirigos, et al., 2010; Elia et al., 2018). The acidification caused
by increased lactate production regulates, in part through nuclear factor
kappa B (NF-κB) signaling, the secretion and activation of hydrolases
such as cathepsins and matrix metallopeptidase 9 (also known as matrix
metalloproteinase 9), which degrade ECM components, supporting tumor
invasion (Elia et al., 2018; Payen, Porporato, Baselet, & Sonveaux, 2016). A
lactate transporter [monocarboxylate transporter 1 (MCT1)]-dependent
stimulation of NF-κB signaling has also been reported in invasive cancer
cells (Elia et al., 2018; Payen et al., 2016, 2017), which possibly coordinates
ECM degradation, alongside induction of EMT (Elia et al., 2018; Payen
et al., 2016). Thus, these studies suggest that glucose metabolism associated
glycolysis and lactate metabolism can regulate signaling pathways that pro-
mote cancer invasion and motility though the upregulation of proteolytic
activity and EMT.
Fig. 12 Metabolic rewiring supports cancer cell invasion by inducing signaling

pathways. These signaling pathways activate cellular program such as EMT and ECM
degradation that are known to support invasion and motility. Enzymes are depicted
in boxes. Green indicates glycolysis, red indicates oxidative mitochondrial metabolism,
magenta indicates glutamine and asparagine metabolism, yellow indicates fatty acid
metabolism, and rose indicates acetate metabolism. Signaling molecules/pathways
are depicted in italics and bright blue. Bold dashed lines indicate regulation, while
fine dashed line depict downregulated metabolic pathways. ACC1, acetyl-CoA carbox-
ylase 1; acetyl-CoA, acetyl-coenzyme A; ACSS2, acyl-coenzyme A synthetase 2; EMT,
epithelial-to-mesenchymal transition; ECM, extracellular matrix; FASN, fatty acid
synthase; FAK, focal adhesion kinase; GRM3, metabotropic glutamate receptor 3;
HIF2a, hypoxia-inducible factor 2a; HK2, hexokinase 2; LACTB, penicillin-binding/B-
lactamase like protein; MCT1, monocarboxylate transporter 1; NF-kB, nuclear factor kappa
B; P, phosphorylation; PGC-1a, peroxisome proliferator-activated receptor gamma
coactivator 1-alpha; PKM2, pyruvate kinase M2; Pyk2, protein-tyrosine kinase 2; ROS, reac-
tive oxygen species; SCD1, stearoyl-CoA desaturase 1; Smad2, Smad family member 2; Src,
proto-oncogene tyrosine-protein kinase; TCF4, transcription factor 4; TGFb, transforming
growth factor b; Wnt, Wnt family member; YAP, yes-associated protein 1; ZEB1, zinc finger
E-box-binding homeobox 1. From Elia, I., Doglioni, G., & Fendt, S. M. (2018). Metabolic hall-
marks of metastasis formation. Trends in Cell Biology, 28(8), 673–684. doi: https://doi.org/
10.1016/j.tcb.2018.04.002.
Another mechanism by which glucose metabolism controls metastatic

spread is through cancer cell secretion of exosomes containing miR-122,
which suppresses glucose metabolism of resident cells in the premetastatic
niche by downregulating PKM and glucose transporter 1 (GLUT1) (Elia
et al., 2018; Fong et al., 2015). This results in increased availability of glu-
cose, which aids the high metabolic needs of the metastasizing breast cancer
cells. Consequently, treatment with anti-miR-122 was reported to signifi-
cantly reduce metastasis formation in xenograft mouse models (Elia et al.,
2018; Fong et al., 2015). This priming of the premetastatic niche could
be particularly important for metastasizing cancer cells arising from highly
glycolytic primary breast cancers (Elia et al., 2016, 2018).
The metabolic profiles of metastatic cells vary as they colonize different
organs (Pascual et al., 2018). This has been reported in murine orthotopic
model-based studies of metastatic breast cancer, where cells show high
expression of coactivator PPARGC1A (peroxisome proliferator-activated
receptor gamma, coactivator 1 alpha; also known as PGC-1α) compared
to the primary breast tumor. PGC-1α regulates the metastatic potential of
CTCs through heightened oxidative phosphorylation activity (LeBleu
et al., 2014; Pascual et al., 2018). However, in a mouse model of prostate
cancer, PGC-1α was reported to act as a metastasis-suppressing factor, fur-
ther highlighting the importance of cancer metabolic heterogeneity within
different tissue-based tumor microenvironments (Pascual et al., 2018;
Torrano et al., 2016). Another study documents that breast cancer cells with
broad metastatic potential (bone, lung and liver) are capable of utilizing both
OXPHOS and glycolysis-dependent metabolic strategies, while liver met-
astatic cells rely on glucose uptake and glycolysis, and lung metastatic cells on
the other hand depend on glutamine uptake and OXPHOS to metastasize
(Dupuy et al., 2015; Pascual et al., 2018). Tumor cells are capable of
hijacking nutrients from the resident cells they encounter as they arrive in
an organ, and this also depends on the nutrient availability, which may vary
significantly between different organs. Accordingly, the availability of spe-
cific nutrients for tumor cells in different organs might contribute unique
metabolic states on metastatic cells (Pascual et al., 2018).
4.2 Lipid metabolism in metastasis

Lipid/fatty acid metabolism has been reported to contribute to the prolifer-
ation of primary tumor lesions (German et al., 2016; Pascual et al., 2018;
Svensson et al., 2016), however several groups indicate that it also regulates
metastasis. Internalization of fatty acids (FAs) is reported as a key aspect of

quiescent MICs which regulates their metastatic spread after dissemination
(Pascual et al., 2017, 2018). These MICs highly express CD36, an FA recep-
tor, reported to be solely involved in the initiation of metastasis in models of
human oral squamous cell carcinoma (OSCC), melanoma and breast cancer
(Pascual et al., 2017, 2018). Furthermore, human CD36+ OSCC metastatic
cells in mouse orthotopic models are extremely responsive to circulating
blood fat levels, and a high-fat diet or stimulation with palmitic acid strongly
augments their metastatic ability (Pascual et al., 2017, 2018). FA uptake by
CD36 and by the FA-binding proteins 1 and 4 (FABP1 and FABP4) is also
known to promote EMT in liver cancer cells, thus regulating their migration
and invasiveness (Nath, Li, Roberts, & Chan, 2015; Pascual et al., 2018).
The enzyme monoacylglycerol lipase (MAGL), and the FFAs it produces,
are reported to be present in increased amounts in aggressive human ovarian
cancer cell lines and in primary ovarian tumors (Nomura et al., 2010; Pascual
et al., 2018). Inhibition of MAGL decreases ovarian tumor growth and
migration, and both of these phenotypes can be rescued by exogenous sup-
ply of FFAs, such as a high-fat diet. These studies highlight the relevance of
dietary lipids in regulation of progression of cancer cells (Nomura et al.,
2010; Pascual et al., 2018).
Cancer cells are also capable of regulating the anabolic/catabolic balance
to meet the increasing metabolic requirements of an aggressive progression
phenotype (Luo et al., 2017). To support this, lipid rafts within cell mem-
brane mediate lipid signaling processes that promote metastasis. Metastatic
cancer cells can hijack lipid metabolism in supporting host cells in the micro-
environment to benefit their colonization (Fig. 13).
Different stages of FA metabolism such as fatty acid synthesis, uptake, and
processing have all been associated with cancer progression. Xenografted
tumors of human breast and colon cancers show increased fatty acid synthe-
sis, which promotes regrowth and metastasis formation (Elia et al., 2018;
Sounni et al., 2014). Both lipid accumulation and free fatty acid uptake
are reported to promote the invasiveness, migration, and progression of can-
cers such as breast and liver cancers (Antalis, Uchida, Buhman, & Siddiqui,
2011; Elia et al., 2018; Mishra & Ambs, 2015), mainly through the induction
of EMT caused by transforming growth factor beta (TGFβ) and the Wnt
family member (Wnt) signaling (Elia et al., 2018; Nath et al., 2015). In addi-
tion, breast cancer cells show decreased expression of mitochondrial protein
penicillin-binding/β-lactamase like protein (LACTB), causing increased
proliferation, and EMT induction, through phospholipid-mediated zinc
Fig. 13 Schematic representation of lipid metabolism implicated in cancer metastasis. Cancer cells fine-tune the anabolic/catabolic balance
to meet the increasing metabolic requirements and lead to aggressive tumor progression. In addition, lipid rafts within cell membranes pro-
vide the platform to mediate lipid signaling that contributes to metastasis. During the progress of metastasis, cancer cells can couple lipid
metabolism with supporting host cells in the microenvironment to benefit their distant metastasis. ACLY, ATP citrate lyase; ACC, acetyl-CoA
carboxylase; ACS, acyl-CoA synthetases; CPT1, carnitine palmitoyl transferase 1; DAG, diacylglycerol; DGAT, diacylglycerol acyltransferase;
ER, endoplasmic reticulum; ETC, electron transport chain; FA, fatty acid; FAO, fatty acid oxidation; FASN, fatty-acid synthase; GPL,
glycerophospholipid; Lyso-PL, lysophospholipid; MAG, monoacylglycerol; MAGL, monoacylglycerol lipase; NADH, nicotinamide adenine
dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phos-
phatidylcholine; PLA2,Phospholipase A2; PLD, phospholipase D; ROS, reactive oxygen species; SCD, stearoyl-CoA desaturases; TG,
triacylglycerol. From Luo, X., Cheng, C., Tan, Z., Li, N., Tang, M., Yang, L., et al. (2017). Emerging roles of lipid metabolism in cancer metastasis.
Molecular Cancer, 16(1), 017–0646. doi: https://doi.org/10.1186/s12943-3.
finger E-box binding homeobox 1 (ZEB1) signaling (Elia et al., 2018;

Keckesova et al., 2017). FA desaturation also correlates with stemness in
ovarian cancer cells via NF-κB signaling (Elia et al., 2018; Li et al.,
2015). A component of FA metabolism is the metabolite acetyl-CoA, an
important donor for protein and histone acetylation. Studies have reported
that inhibition of the fatty acid synthesis enzyme acetylCoA carboxylase 1
resulted in acetylCoA accumulation (Elia et al., 2018; Rios Garcia et al.,
2017), which promoted EMT through Smad2 signaling.
4.3 Epigenetic regulation of metastatic metabolic rewiring

Recent studies have enhanced our understanding of metastatic signaling,
however, the molecular mechanisms that underlie chromatin remodeling
during metastasis are still largely unexplored. Despite this deficiency, most
researchers agree that these epigenetic mechanisms are regulated by the local
and systemic availability of metabolites in the cancer cells (Fig. 11) (Pascual
et al., 2018). These metabolites behave as cofactors or substrates for enzymes
involved in the epigenetic regulation of tumor cells (Fan, Krautkramer,
Feldman, & Denu, 2015; Pascual et al., 2018). Some studies report that
enzymes producing some of these metabolic substrates are capable of col-
ocalizing with the epigenetic apparatus in the nucleus to create chromatin
metabolic microdomains (Katada, Imhof, & Sassone-Corsi, 2012; Pascual
et al., 2018). These microdomains would then enable the epigenetic regu-
lation of specific metabolic states in cancer cells.
Histone acetyltransferases (HATs) transfer acetyl-CoA-derived acetyl
moieties to lysine residues on histone tails. Histone acetylation opens up
the chromatin promoting the transcription of genes that are located within
the acetylated chromatin region. The enzyme ATP citrate lyase (ACLY) can
control global transcription through chromatin remodeling in the nucleus
(Pascual et al., 2018; Wellen et al., 2009). ACLY can acetylate chromatin
regions comprised of genes involved in glucose metabolism, such as the glu-
cose transporter 4 (GLUT4), HK2, PFK1 and LDHA genes. A second
enzyme, ACSS2, which regulates generation of acetyl-CoA from acetate,
can regulate the integration of acetyl-CoA into histones (Mews et al.,
2017; Pascual et al., 2018), which can have either a promoting or inhibitory
effect on tumor progression, depending on tumor type (Comerford et al.,
2014; Pascual et al., 2018).
Methionine, an essential amino acid, is linked to the activities of HMTs
and DNA methyltransferases (DNMTs), which are strongly regulated by the
nutritional condition of the cells. Diet-dependent changes in histone meth-

ylation in colorectal adenomas have been reported (Pascual et al., 2018;
Pufulete et al., 2005). A correlation exists between increased metastatic
colonization and expression of histone H3 trimethylation in patient-derived
xenograft models of melanoma (Pascual et al., 2018; Shi et al., 2017). While
these regions of hyper- and hypomethylation in cancer are not clearly defined,
they are strongly regulated by metabolism. The primary methyl group donor
for DNA is SAM, which is generated in the methionine cycle from methionine
and ATP. α-Ketoglutarate a TCA cycle intermediate is another contributor of
DNA demethylation, whereas the TCA-cycle-derived metabolites succinate,
fumarate and 2-hydroxyglutarate act as competitive TET inhibitors emphasiz-
ing the complex metabolic control of tumor cells.
4.4 Regulation of EMT by oncogenic metabolism

Epithelial-mesenchymal transition (EMT) is crucial for the development of
metastasis (Wei, Qian, Yu, & Wong, 2020). EMT causes epithelial cells to
lose their polarity, epithelial markers and gain the capacity to spread into
neighboring stroma along with expression of mesenchymal markers vimentin
and N-cadherin (Lamouille, Xu, & Derynck, 2014; Pastushenko & Blanpain,
2019; Wei et al., 2020). Hypoxia and inflammation (Lamouille et al., 2014;
Pastushenko & Blanpain, 2019; Wei et al., 2020), are reported to cause
EMT. 2-HG an oncometabolite present in elevated levels in isocitrate dehy-
drogenase 1 or 2 (IDH1/2) mutant tumor cells, is a promoter of ZEB1-
mediated EMT (Grassian et al., 2012; Wei et al., 2020). Other oncometabolites
such as succinate and fumarate also support SNAIL-, TWIST- and ZEB-
mediated EMT via the inhibition of DNA and/or histone demethylases.
Metabolite α-KG promotes TETs-mediated promoter demethylation and
re-expression of the antimetastatic miR-200 cluster, which inhibits ZEB1/
CtBP1-MMP3 axis-mediated EMT signaling (Atlante et al., 2018; Wei
et al., 2020). The balance of α-KG-to-succinate/fumarate/2-HG ratios are
thus one of the key regulators of EMT and metastasis. Acetyl-CoA which pro-
motes histone acetylation can stimulate TWIST2 expression which then pro-
motes increased N-cadherin expression and reduced E-cadherin, thereby
contributing to EMT and metastasis in animal models. This hypothesis is
supported by studies which employed acetate supplementation to increase
acetyl-CoA resulting in TWIST2-mediated EMT, highlighting the impor-
tance of this metabolite in metastasis (Lu et al., 2019; Wei et al., 2020).
Acetyl-CoA also facilitates acetylation and nuclear translocation of Smad2
transcription factor to mediate SNAIL1/2, EMT, and tumor metastasis.
In support of these findings, silencing of ACLY to suppress acetyl-CoA biosyn-

thesis reverses EMT markers induced by ACC1 silencing, accompanied by
decreased invasiveness in tumor cells (Rios Garcia et al., 2017). However,
ACSS2 overexpression in HCC causes acetylation of HIF-2α leading to sup-
pression of EMT under hypoxic conditions (Sun et al., 2017). This argues that
acetyl-CoA mediated regulation of EMT is highly dependent on the target pro-
teins and the tumor microenvironment. Cholesterol a component of FA
metabolism, helps in the formation of lipid rafts on the cell membrane to reg-
ulate the activities of cell surface receptors. Altered cholesterol flux causes mem-
brane fluidity leading to decreased cell motility, stem cell-like properties, EMT,
and thus, metastasis (Wei et al., 2020; Zhao et al., 2016). In support of this the-
ory, researchers have shown that cholesterol treatment in vitro results in the
development of mesenchymal-like phenotype in metastatic prostate cancer
cells in vitro, and cholesterol-fed mice developed significantly more metastatic
liver nodules compared to mice fed a normal chow diet ( Jiang et al., 2019).
Cholesterol induced lipid-rafts are reported to regulate adipocyte plasma
membrane-associated proteins, which together with epidermal growth fac-
tor receptor substrate 15-related protein (EPS15R), decreased endocytosis-
mediated EGFR degradation, leading to activation of ERK1/2 to trigger
EMT (Wei et al., 2020). Thus, various metabolic pathways and their metabo-
lites can regulate EMT in cancer cells, both in vitro and in vivo.
4.5 Metabolism of circulating cancer cells

It is essential for metastatic cancer cells to survive while circulating in the
body after dissemination. Cancer cells exhibit decreased cell-matrix interac-
tion which is decreased even more in the circulation (Elia et al., 2018).
Normal cells undergo anoikis after detachment from the matrix (Dey
et al., 2015; Hawk & Schafer, 2018). The presence of elevated antioxidant
mechanisms helps the cancer cells to survive after matrix detachment as well
as in the circulation (Fig. 10). Circulating tumor cells show an increase in
PGC1α-dependency (LeBleu et al., 2014), which helps in maintaining
ROS homeostasis (Baldelli, Aquilano, & Ciriolo, 2014), which decreases
anoikis. When oncogenes like Erbb2 are overexpressed in mammary
epithelial cells they are also able to survive matrix detachment (Schafer
et al., 2009). Erbb2 signaling is reported to activate the pentose phosphate
pathway, which generates NADPH, necessary for recycling the ROS scav-
enger glutathione. This leads to the restoration of energy processes affected
by ROS accumulation leading to increased cancer cell survival during
matrix detachment (Schafer et al., 2009). Matrix detachment is also reported
to decrease glucose oxidation in breast cancer cells, reducing mitochondrial

ROS generation (Kamarajugadda et al., 2012) while overexpression of the
mitochondrial pyruvate carrier needed for glucose oxidation, is reported to
negatively affect matrix-detached colon cancer cells (Schell et al., 2014).
Most adherent, normoxic, and respiration-competent cancer cells exhibit
reduced conversion of α-ketoglutarate to citrate (reductive carboxylation)
(Fendt, 2019; Fendt, Bell, Keibler, Olenchock, et al., 2013; Fendt, Bell,
Keibler, Davidson, et al., 2013; Metallo et al., 2012; Mullen et al., 2012).
However, matrix-detached lung, colon, and breast cancer cells rewire their
metabolism and utilize a cross compartment α-ketoglutarate-citrate cycle,
merging oxidative decarboxylation in the mitochondria with reductive car-
boxylation in the cytosol (Elia et al., 2018; Jiang et al., 2016). This leads to
increased enriched antioxidant defense in the mitochondria aiding the survival
of the matrix-detached cancer cells. The importance of ROS scavenging for
the survival of circulating tumor cells and metastasis formation is evident fol-
lowing treatment of different melanoma mouse models with the antioxidant
N-acetylcysteine, which results in an increased number of melanoma cells in
circulation and lymph node metastasis (Elia et al., 2018; Le Gal et al., 2015;
Piskounova et al., 2015). In this way, cancer cells survive anoikis through
various antioxidant pathways, reducing ROS production, and redirecting
scavenging capacity to the mitochondria. ROS scavenging is also capable
of promoting the stemness of cancer cells, resulting in increased metastasis
(Elia et al., 2018; Monteiro & Fodde, 2010). Breast cancer cells in comparison
to mammary epithelial cells, exhibit an increased EMT phenotype after matrix
detachment (Elia et al., 2017, 2018), which can inhibit the gluconeogenic
enzyme fructose bisphosphatase 1 (FBP1), reducing oxidative metabolism,
through a largely unknown mechanism (Dong et al., 2013; Elia et al.,
2018). As a result, mitochondrial ROS production is decreased, helping
the interaction of β-catenin with TCF4, thereby promoting stemness through
the Wnt signaling cascade (Dong et al., 2013). These various studies show the
significance of metabolic plasticity which influences metastatic cancer starting
from tumorigenesis to the various stages of cancer progression and finally to
metastasis (Fig. 10) (Pascual et al., 2018).
5. Tumor-microenvironment and metabolic crosstalk

in cancer progression
The tumor microenvironment is an environment created by the
tumor and controlled by tumor-induced interactions. The microenviron-
ment of the developing tumor is composed of tumor cells, the tumor stroma,
blood vessels, infiltrating inflammatory cells, a variety of associated tissue

cells and the nutritional environment created by the interaction of these
components of the microenvironment. The tumor microenvironment plays
a prominent role in cancer progression. This often includes the metabolic
regulation of this microenvironment as well as its components.
5.1 Hypoxia and cancer cell metabolism

Hypoxia is defined as a condition where deficient oxygen levels results in
cellular changes mainly driven by hypoxia inducible factor (HIF) signaling
(Madan et al., 2020). HIFs are a family of transcription factors consisting of
HIF-1, HIF-2, and HIF-3. They all consist of an α-subunit that is stabilized
by hypoxia and a constitutively expressed β-subunit (ARNT) (Madan et al.,
2020). HIFs regulate the cellular transcriptome, thereby regulating metab-
olism, glucose uptake, proliferation, differentiation, and survival as well as
angiogenesis and erythropoiesis (Madan et al., 2020). Some studies have
shown that HIF-1α may promote opposite roles in tumor progression
(Madan et al., 2020). Activated HIF-1α can induce EMT in cancer cells
which in turn promotes invasion, stemness, and resistance to chemotherapy
(Madan et al., 2020). HIF-1α is also capable of promoting cancer migration
by regulation of expression of enzymes that regulate the arrangement of col-
lagen fibers and integrin signaling (Madan et al., 2020). Hypoxia induces
endothelial cell contraction, resulting in leaky vessels which spread the
metastatic cancer cells through blood and lymphatic vessels (Madan et al.,
2020). HIF-1α has been reported to be overexpressed in several types of
cancer, such as breast, colon, gastric, lung, skin, ovarian, pancreatic, and
prostate, compared to their respective normal tissues (Madan et al., 2020).
HIF-1 can activate the multidrug resistance 1 (MDR1) gene, thereby induc-
ing chemoresistance (Madan et al., 2020). Hypoxia has been reported to
regulate lipid metabolism by encouraging the cells to utilize alternative car-
bon sources, such as acetate, to sustain FA synthesis and tumor growth. This
lipid metabolic switch is regulated by HIF through transcriptional control of
acetyl-CoA synthetase-2 (ACSS2), and by ACSS2 copy-number gains
(Pascual et al., 2018).
Hypoxia can also regulate cell competition via Wnt, BMP, and Myc
(Madan et al., 2020). HIF-1α can thus control glycolysis, glycogenolysis,
glycogen synthesis, lipid and glutamine based metabolism, demonstrating
its importance in metabolic regulation of cancer at various stages of cancer,
starting from initiation to metastasis and resistance to therapy (Madan
et al., 2020).
5.2 Metabolic coupling between tumor cells and stroma

Tumor cells possess an important and interesting ability to hijack the metab-
olism of their tumor microenvironment to obtain abundant supplies of
energy and resources, through a process known as metabolic coupling
(Pascual et al., 2018). Metabolic coupling is possible either between tumor
cells or between tumor and stromal cells. Metastatic ovarian cancer cells
stimulate the colonized fat pad to release stored lipids which supports the
tumor’s need of FAs for energetic and biosynthetic functions (Nieman
et al., 2011; Pascual et al., 2018). Studies in mouse models of chronic mye-
loid leukemia (CML) and primary human CML samples, demonstrate the
existence of subpopulations of leukemia stem cells (LSCs), called GAT-
LSCs, which collaborate with the gonadal adipose tissue (GAT) after che-
motherapy. GAT-LSCs secrete pro-inflammatory cytokines (IL-1α and
TNF-α), to induce lipolysis in the surrounding GAT adipocytes, leading
to the uptake and oxidation of free FAs (FFAs) by the FA receptor
CD36. This metabolic coupling also supports GAT-LSCs with enough
energy and resources to resist chemotherapy and therefore this process is
critical in leukemia relapse (Pascual et al., 2018; Ye et al., 2016).
Cancer metabolism is capable of suppressing the antitumor immune
response through: metabolite excretion; and/or nutrient deprivation
(Lunt & Fendt, 2018). Cancer cells secrete metabolites (such as lactate
(Brand et al., 2016; Lunt & Fendt, 2018) and FAs (Lunt & Fendt, 2018;
Ma et al., 2016)) which inhibit proliferation and/or effector function of
anti-tumor lymphocytes (while promoting proliferation and the regulator
function of pro-tumor lymphocytes (Angelin et al., 2017; Lunt & Fendt,
2018)). In addition, these secreted metabolites (such as lactate) can repro-
gram macrophages from an anti-tumor to a pro-tumor polarization
(Colegio et al., 2014; Lunt & Fendt, 2018). In the second type of immune
suppressing strategy, cancer cells exhaust the availability of nutrients that
anti-tumor lymphocytes require for proliferation and/or effector functions
(Chang et al., 2015; Ho et al., 2015; Lunt & Fendt, 2018), through either
direct consumption or by an indirect means such as secretion of nutrient
degradation enzymes by tumor-associated macrophages or tolerogenic-
dendritic cells to the microenvironment (Lunt & Fendt, 2018).
In addition to the studies described above, mouse models of both mel-
anoma (B16) and Lewis lung carcinoma (LLC) develop a hyper-glycolytic
intra-tumor endothelium that supports metastatic spreading (Cantelmo
et al., 2016). Similarly, the inhibition of the glycolytic activator PFKFB3
(6-phosphofructo-2-kinase) in endothelial cells leads to decreased cancer

cell intravasation and metastasis through the normalization of the tumor ves-
sel architecture (Cantelmo et al., 2016; Pascual et al., 2018). These findings
suggest development of new therapeutic strategies to prevent the coloniza-
tion of distant sites by metastatic cells is possible by inhibiting the metabolic
crosstalk between cancer cells and their environment.
5.3 Metabolic preconditioning of the metastatic niche

One of the most interesting phenomenon in the metastatic process is the
preconditioning of metastatic niches prior to the arrival of disseminated
cancer cells from primary tumor sites (Kaplan et al., 2005; Pascual et al.,
2018; Peinado et al., 2017). Primary tumors secrete molecules to prepare
a permissive premetastatic niche that favors metastatic seeding by shaping
the stromal, immune cell, and/or matrix composition of the niche environ-
ment (Elia et al., 2018; Liu & Cao, 2016). Several studies support the
hypothesis that specific metabolic changes are associated with the establish-
ment of these niches. For example, the pro-metastatic factors secreted by the
primary tumors can be transferred to neighboring or distant non-tumor cells
through exosomes (Fig. 10) (Pascual et al., 2018; Peinado et al., 2017).
Human xenograft model studies show that circulating breast-cancer-derived
vesicles that contain the microRNA miR-122 can inhibit the expression of
glucose transporter 1 (GLUT1) and pyruvate kinase M1/M2 (PKM1/2) iso-
zymes to reduce glucose uptake in normal lung and brain cells. This increases
the availability of glucose for the incoming metastatic cancer cells (Fong
et al., 2015; Pascual et al., 2018). Studies using disseminated human colorec-
tal cancer cells in a mouse model found secretion of protein creatine kinase
brain-type (CKB) by the cancer cells in the liver, inducing the conversion of
extracellular ATP and hepatic creatine into phosphocreatine. This molecule
is then taken up by the metastatic cells via the creatine transporter, SLC6A8
driving the generation of ATP within metastatic cells. This supports the ele-
vated needs of energy in metastatic cells and aids in colonization of the liver
(Loo et al., 2015; Pascual et al., 2018).
6. Overlap in metabolic signatures of cancer cells

and stem cells
Cancer cells and stem cells retain the ability to re-enter the cell cycle
and proliferate, which is in sharp contrast with the behavior of terminally
differentiated cells (Intlekofer & Finley, 2019). Studies show that the
intermediates of central metabolic pathways function as key regulators of

cell-differentiation “decisions,” which are also highly relevant to both onco-
genesis and normal development. These metabolic processes show a great
degree of overlap in the functionally of these two different cell types.
6.1 Metabolic strategies used by cancer cells and pluripotent

stem cells
Both pluripotent stem cells (PSCs) and cancer cells have the capacity to pro-
liferate indefinitely in culture and are both highly dependent on exogenous
glucose and glutamine (Carey, Finley, Cross, Allis, & Thompson, 2015;
Intlekofer & Finley, 2019; Tohyama et al., 2016). Pluripotent stem cells
irrespective of their cell of origin or stage of pluripotency, utilize aerobic
glycolysis, consuming high levels of glucose and secreting large quantities
of lactate, which is not observed in the slower growing differentiated cells
(Chung et al., 2007; Gu et al., 2016; Intlekofer & Finley, 2019; Zhang
et al., 2011; Zhou, Li, et al., 2012). This glycolytic flux depends on stemness
and is also reversible. Lactic acid production due to glycolysis is decreased
early during PSC differentiation (Cliff et al., 2017; Gu et al., 2016;
Intlekofer & Finley, 2019; Moussaieff et al., 2015; Zhang et al., 2011)
and this phenotype is similarly reacquired during the reprograming of differ-
entiated cells into the pluripotent state (Folmes et al., 2011; Intlekofer &
Finley, 2019; Mathieu et al., 2014; Panopoulos et al., 2012). In the same man-
ner, impairing glycolytic metabolism damages the pluripotent reprogramming
signaling as well as causing a loss in the pluripotent state (Cliff et al., 2017;
Folmes et al., 2011; Gu et al., 2016; Intlekofer & Finley, 2019; Mathieu
et al., 2014; Moussaieff et al., 2015; Panopoulos et al., 2012). Transcription
factors that regulate the pluripotent state may also directly regulate metabolic
pathways: such as Oct4 which binds loci encoding glycolytic genes to
promote glycolysis, as well as stemness (Intlekofer & Finley, 2019; Kim
et al., 2015). To add more complexity, this phenomenon is not true for all
situations, for example while human PSC differentiation to mesoderm and
endoderm reduces glycolytic flux, PSC differentiation to early neuroectoderm
does not induce a similar effect (Cliff et al., 2017; Intlekofer & Finley, 2019).
This emphasizes the importance of further research to clarify the connection
between aerobic glycolysis and pluripotency and whether these processes are
the result of bioenergetic constraints of particular cell types or the result of
modified metabolite accumulation that can determine cell fate. PSCs exhibit
high mitochondrial substrate oxidation that generates ROS facilitating differ-
entiation and damaging effects. PSCs need to eliminate reduced electrons in
the form of lactate to resist spontaneous differentiation or apoptosis

(Intlekofer & Finley, 2019; Madden, Davila-Kruger, Melov, & Bredesen,
2011; Setoguchi, TeSlaa, Koehler, & Teitell, 2016). In support of this hypoth-
esis, it is reported that the metabolome of ESCs becomes more oxidized after
differentiation (Intlekofer & Finley, 2019; Yanes et al., 2010).
CSCs are cancer cells that have a lot in common with stem cells. Several
reports suggest that CSCs are more glycolytic than other differentiated can-
cer cells in vitro and in vivo (Peiris-Pages et al., 2016). These studies were per-
formed in many tumor types including osteosarcoma, glioblastoma, breast
cancer, lung cancer, ovarian cancer and colon cancer (Ciavardelli et al.,
2014; Emmink et al., 2013; Liao, Hsu, et al., 2014; Liao, Qian, et al.,
2014; Peiris-Pages et al., 2016; Zhou et al., 2011). There is also growing
evidence indicating that CSCs have a preference for mitochondrial oxidative
metabolism (De Luca et al., 2015; Janiszewska et al., 2012; Lagadinou et al.,
2013; Peiris-Pages et al., 2016; Sancho, Barneda, & Heeschen, 2016; Vlashi
et al., 2011).
6.2 Metabolic regulation of chromatin and differentiation

Metabolites not only act as critical substrates to drive cell growth and pro-
liferation, but they can also actively influence differentiation in both stem
cells and cancer cells (Intlekofer & Finley, 2019; Pavlova & Thompson,
2016; Schvartzman, Thompson, & Finley, 2018). Several key metabolites
function as obligate substrates or co-factors for enzymes that regulate the
modification of DNA and histones. This biochemical relationship between
metabolites and chromatin-modifying enzymes suggests that metabolites can
regulate the fate of cells through chromatin modifications, which in turn
regulate gene expression programs involved in self-renewal and lineage dif-
ferentiation (Intlekofer & Finley, 2019; Reid, Dai, & Locasale, 2017). In
support of this hypothesis it has been reported that acetylation of histones
and methylation of both histones and DNA are expressly responsive to met-
abolic inputs (Fig. 14) (Intlekofer & Finley, 2019; Su, Wellen, & Rabinowitz,
2016).
6.3 Metabolic heterogeneity of cancer stem cells

Metabolism in cancer stem cells is an area of extensive exploration with many
unanswered questions (Deshmukh, Deshpande, Arfuso, Newsholme, &
Dharmarajan, 2016). It seems unlikely that a single metabolic signature will
be characteristic of all cancer stem cells, just as there is no single metabolic
Fig. 14 Metabolic regulation of epigenetic mechanisms. Metabolism and epigenetic

landscape interplay. (A) Models of cooperation between metabolism and epigenome:
(i) Inhibitor metabolite production and chromatin regulation; (ii) nutrient sensing and
chromatin regulation; (iii) localized metabolite production and chromatin regulation.
(B) Methionine cycle is connected to the folate cycles, where serine, and glycine, provide
one-carbon units to tetrahydrofolate for transfer to homocysteine. Succinate, fumarate,
and 2-hydroxyglutarate act as competitive inhibitors thereby leading to the accumula-
tion of methyl marks. During histone acetylation, histone acetyltransferases transfer
acetyl groups from acetyl-coenzyme A to histones. Acetyl Coenzyme A is generated
from citrate, pyruvate, and acetate. In addition, class I, II, and IV histone deacetylases
can produce acetate, which can also be utilized to produce Acetyl Coenzyme. Panel
(A): From Miranda-Gonçalves, V., Lameirinhas, A., Henrique, R., & Jerónimo, C. (2018).
Metabolism and epigenetic interplay in cancer: Regulation and putative therapeutic
targets. Frontiers in Genetics, 9, 427. doi: https://doi.org/10.3389/fgene.2018.00427.
phenotype of adult stem cells from which these cancer stem cells may arise
due to mutations (Batlle & Clevers, 2017; Intlekofer & Finley, 2019;
Snyder, Reed-Newman, Arnold, Thomas, & Anant, 2018). Conflicting
research results have been obtained indicating that cancer stem cells exhibit
decreased mitochondrial function and increased dependence on glycolytic
flux (Chen, Sun, & Chen, 2016; Dong et al., 2013; Intlekofer & Finley,
2019; Li et al., 2009; Saito, Chapple, Lin, Kitano, & Nakada, 2015; Wang
et al., 2014; Zhou et al., 2011), whereas other studies report the opposite effect
with increased dependence on mitochondrial function and oxidative phos-

phorylation (Intlekofer & Finley, 2019; Janiszewska et al., 2012; Lagadinou
et al., 2013; Sancho et al., 2016; Vlashi et al., 2011). Lipid metabolism-
based heterogeneity also plays an important role in cancer stem cell mainte-
nance by supplying bioenergetic substrates and regulating cell fate decisions
(Chen, Sun, & Chen, 2016; Chen, Uthaya Kumar, et al., 2016;
Intlekofer & Finley, 2019; Li et al., 2017; Pascual et al., 2017; Ye et al.,
2016). Cell lineage, tissue of origin, environmental niche and dynamic cellular
phenotypes all contribute to a heterogeneous metabolic profile.
7. Metabolism and cancer therapy

Cancer cells generally retain metabolic flexibility (plasticity) and can
resist therapeutic treatment by undergoing metabolic reprogramming.
Synthetic lethal combination therapies are therefore essential to attack the
liabilities of each metabolic type to obtain therapeutic benefit.
7.1 Chemotherapeutically targeting metastasis through

metabolism
Chemotherapeutic strategies that target metabolism have been considered
effective cancer treatments for a long time, which suggests that targeting
malignant metabolism may be possible (Columbano & Giordano, 2017;
Luengo, Gui, & Vander Heiden, 2017; Lunt & Fendt, 2018). New thera-
peutic strategies to exploit metabolism are currently being evaluated in
pre-clinical models or clinical trials. The early clinical success of antifolates
resulted in the design and engineering of a new class of drugs known as
“antimetabolites.” Antimetabolites are small molecules that mimic nucleo-
tide metabolites and consequently inhibit the activity of enzymes required
for nucleotide base synthesis (Table 2). Some well-known examples of
antimetabolites are the purine analogues 6-mercaptopurine (6-MP) and
6-thioguanine (6-TG), which inhibits 5-phosphoribosyl-1-pyrophosphatase
(PRPP) amidotransferase, gemcitabine and cytarabine (Luengo et al., 2017).
Extensive research has been performed to target the increased glycolysis
and lactate production and secretion that is characteristic of cancer cells
(Doherty & Cleveland, 2013; Hamanaka & Chandel, 2012; Hay, 2016;
Pelicano, Martin, Xu, & Huang, 2006; Zhao, Butler, & Tan, 2013). One
such inhibitor is 2-deoxyglucose (2-DG) (Wick, Drury, Nakada, &
Wolfe, 1957). 2-DG acts as a glucose analogue and is phosphorylated by
hexokinase to produce 2-deoxyglucose-6-phosphate, which cannot be
Table 2 Drugs/compounds targeting different proteins/enzymes of the metabolic pathways.
Target proteins/
Pathways enzymes or metabolites Drugs/compounds Cancer/tumor type Clinical trial status
Signaling proteins and transcription factors
mTORC1 Temsirolimus and Metastatic/non-metastatic solid tumors US FDA approved
Everolimus
Ridaforolimus and other Pancreatic, endometrial and Phase I/II
rapalogues glioblastoma; lymphoma.
mTORC1 and Torin1 and PP242 – Preclinical
mTORC2
HIF1α PX-478 Advanced solid tumor and lymphoma Phase I
Acriflavine – Preclinical
Hypoxia Tirapazamine and other Cervical, SCLC, NSCLC Phase III
bioreductive compounds
Hypoxia, VEGF and Bevacizumab Malignant glioma, NSCLC, ovarian US FDA approved
VEGFR and colorectal
IGF1R Dalotuzumab (MK-0646), Solid tumors of NSCLC, pancreatic, Phase I/II
BIIB022, AVE1642, etc. hepatocellular carcinoma (HCC) and
metastatic breast cancer
PI3K and mTOR BEZ235, XL765, SF1126 Malignant glioma and NSCLC Phase I/II
and BGT226
PI3K GDC-0941 and PX866 Metastatic breast cancer and non- Phase I
Hodgkin’s lymphoma
AKT Perifosine and GSK690693 Renal cancer, NSCLC and lymphoma Phase I/II
AMPK and Complex I Metformin Solid tumors and lymphoma US FDA approved
(mitochondrial)
Metabolic pathway enzymes
Nucleotide DNA and RNA 5-FU, cytarabine and Different types of tumors US FDA approved
biosynthesis synthesis methotrexate
pathway
DNA synthesis Folate, choline, methionine Lab studies
Methyltransferases Betaine, selected B Lab studies
vitamins, Flavonoids,
EGCG, genistein
Histone deacetylases Butyrate, sulforaphane, Lab studies
(HDAC) Allylmercaptan,
3,3-Diindolylmethane
Histone acetyltranferase Anacardic acid, garcinol,
Curcumin, EGCG,
Genistein
Acetylation of Butyrate, cambinol,
non-histone proteins Dihydrocoumarin,
genistein
Glycolysis GLUT1 Phloretin Colon cancer and leukemia –
pathway
GLUT1 WZB117 Lung cancer and breast cancer –
Continued
Table 2 Drugs/compounds targeting different proteins/enzymes of the metabolic pathways.—cont’d
Target proteins/
Pathways enzymes or metabolites Drugs/compounds Cancer/tumor type Clinical trial status
GLUT4 Ritonavir Multiple myeloma –
Hexokinase 2-Deoxyglucose (2-DG) Leukemia, cervical cancer, PhaseI/II
hepatocarcinoma, breast cancer, small
lung cancer, lymphoma and prostate
cancer
Hexokinase Lonidamine (LND) Benign prostatic hyperplasia, leukemia Phase III
and lymphoma
3-Bromopyruvate (3- Leukemia, multiple myeloma, colon Preclinical
BrPA) cancer and leukemia
Pyruvate kinase M2 shRNA Lung cancer –
(PKM2)
Pyruvate kinase (PK) TLN-232 Metastatic melanoma and renal cell Phase II
carcinoma
Lactate dehydrogenase Oxamate Breast cancer
(LDHA)
Pentose Glucose-6-phosphate Resveratrol Colon cancer
phosphate dehydrogenase
pathway (PPP) (G6PDH)
Transketolase (TK) Oxythiamine (OT) Colon cancer
G6PDH and TK Avemar Jurkat T cells (Leukemia)
G6PDH, 6PGDH and Combination of arginine Human hepatoma cell lines (HA2T/
Transaldolase TA and ascorbic acid VGH)
G6PDH, also depletion Dehydroepiandrosterone Indirect study on polycystic ovary
of ribose-5-phosphate (DHEA) syndrome
(R-5P)
TCA cycle Pyruvate dehydrogenase siRNA Cervical cancer and breast cancer
kinase (PDK3)
Pyruvate dehydrogenase Dichloroacetate (DCA) Fibrosarcoma, colon cancer, lung
kinase (PDK1) cancer, squamous cell carcinoma and
prostate cancer
Fatty acid FASN Cerulenin and C75 Breast cancer
synthesis
Orlistat Breast and pancreatic cancer Preclinical
ATP-citrate lyase SB-204990 – Preclinical
Amino acid Glutamine Phenylacetate Brain tumors Phase II
metabolism
Asparagine Asparaginase and Acute lymphoblastic leukemia (ALL), Phase II/III
pathway
pegasparaginase T-cell lymphoma (TCL) and B-cell
lymphoma (BCL)
Arginine Arginine deiminase Metastatic melanoma and Phase I/II
hepatocellular carcinoma
From Rahman, M., & Hasan, M. R. (2015). Cancer metabolism and drug resistance. Metabolites, 5(4), 571–600. doi: https://doi.org/10.3390/metabo5040571.
further metabolized in cells. This results in the competitive inhibition of

hexokinase to target glucose uptake in cancer cells (Luengo et al., 2017).
Several preclinical studies have reported the effectiveness of 2-DG in
decreasing cancer cell proliferation (Zhang et al., 2014), however, the use
of this drug was limited by toxicity promoting hypoglycemic symptoms
(Landau, Laszlo, Stengle, & Burk, 1958). Recent clinical trials report that
lower non-toxic doses cannot inhibit disease progression (Raez et al., 2013;
Stein et al., 2010). The failure and toxicity of 2-DG has also occurred in most
of the other aerobic glycolysis targeting effects. Studies that show success in
targeting glucose uptake or lactate production in preclinical models (Hay,
2016; Luengo et al., 2017; Shim et al., 1997), unfortunately do not replicate
this success in clinical settings (Vander Heiden & DeBerardinis, 2017).
Another interesting area of therapy targeting involves acidification.
Highly glycolytic cancer cells prevent intracellular acidification by excreting
the glycolytic end-products lactate and H+ via the monocarboxylate trans-
porters 1 (MCT1) and 4 (MCT4) (Luengo et al., 2017). The clinical drug
syrosingopine can significantly inhibit the lactate transporters MCT1 and
MCT4 (Luengo et al., 2017). The combination of syrosingopine and met-
formin has been shown to potentiate metformin’s anti-cancer efficacy
(Luengo et al., 2017). Simultaneous inhibition of hypoxia-induced carbonic
anhydrase IX (CAIX) and monocarboxylate transporter 4 (MCT4) results in
acidification of intracellular pH (pHi), which can be further enhanced with
inhibition of Na+/H + exchanger 1 (NHE1) (Parks, Chiche, & Pouyssegur,
2013). MCT inhibition leads to an accumulation of cellular lactate, which
would then inhibit glycolysis, resulting in decreased cellular ATP levels.
This metabolic stress could be further improved with a combinatorial
treatment of metformin or phenformin to inhibit mitochondrial ATP pro-
duction causing metabolic catastrophe (Parks et al., 2013). Treatment
strategies using proton pump inhibitors (PPIs) would impair lysosomal
pH to inhibit mTOR complex 1 (mTORC1) signaling (Parks et al.,
2013) and thus inhibit the protective autophagy necessary for cancer
growth and progression (Talukdar et al., 2018). Inhibition of L-type amino
acid transporter 1 (LAT1) would result in the impairment of the amino
acid uptake pathway, which could further interfere with mTORC1
signaling suggesting possible combination strategies (Parks et al., 2013).
Combinatorial treatments targeting pHi-regulating capacity with inhibi-
tors of crucial metabolic pathways, would in principle cause even highly
aggressive cancer cells to enter metabolic catastrophe-mediated death
(Parks et al., 2013).
Inhibitors of mutant IDH1 and IDH2 enzyme activity are also being
designed and assessed for antitumor efficacy (Dang, Yen, & Attar, 2016). AGI-
5198 was one of the first inhibitors of mutant IDH1. AGI-5198 decreases
intratumoral D-2HG levels, stimulates glial cell differentiation, and suppresses
growth of IDH1-mutant human glioma cells in a xenograft model (Luengo
et al., 2017; Rohle et al., 2013). AG-221 or enasidenib, an inhibitor of mutant
IDH2, provides survival benefit in a mouse model of IDH2-mutant AML
(Quivoron et al., 2014; Yen et al., 2017) and this drug became the first inhib-
itor of mutant IDH to successfully enter clinical trials in 2014.
Most studies focused on inhibiting glutaminolysis clinically have prior-
itized targeting of glutaminase. This process is regulated by two genes, GLS
and GLS2, and targeting the enzymes encoded by these genes with pharma-
cological agents results in decreased cancer cell proliferation both in vitro and
in vivo models (Gross et al., 2014; Jacque et al., 2015; Le Gal et al., 2015;
Luengo et al., 2017; Nguyen & Durán, 2018; Xiang et al., 2015). CB-839
is a glutaminase inhibitor that is being assessed in clinical trials as a potential
drug. It has been suggested that GLS2 activity can be tumor suppressive
(Hu et al., 2010), which could affect the efficacy of glutaminase inhibitors
as chemotherapeutic agents.
Since cancer cells are highly dependent on serine, de novo serine synthesis
could be a prime target for cancer therapy. Loss of PHGDH is reported to be
toxic to tumor cells expressing either PHGDH amplification or high serine
biosynthetic flux (Locasale et al., 2011), and inhibitors targeting PHGDH have
been shown to inhibit serine synthesis and tumor proliferation both in vitro and
in vivo in preclinical cancer models (Luengo et al., 2017; Mullarky et al., 2016;
Pacold et al., 2016). However, inhibitors of PHGDH could have serious side
effects, since de novo serine synthesis has an important physiological role in the
central nervous system (Furuya, 2008) and it is reported that PHGDH-
deficient mice exhibit severe brain morphogenesis defects (Yoshida et al.,
2004). Small molecule drugs with decreased target distribution in normal
tissues may be more effective for cancer therapy.
Several research groups have worked on targeting FA synthesis (Currie,
Schulze, Zechner, Walther, & Farese Jr., 2013), with efforts to inhibit cyto-
solic acetyl-CoA availability via ACLY inhibition as well as direct targeting of
the enzymes ACC and FASN. Since ACLY activity is reported to be higher in
cancers (Migita et al., 2008), and inhibition of ACLY either genetically or
chemically prevents xenograft tumor formation and proliferation (Adam
et al., 2013; Bauer, Hatzivassiliou, Zhao, Andreadis, & Thompson, 2005;
Migita et al., 2008) this could have potential clinical utility. Studies involving
ACC knockdown resulted in apoptotic cell death in cancer cell lines

(Brusselmans, De Schrijver, Verhoeven, & Swinnen, 2005; Chajès,
Cambot, Moreau, Lenoir, & Joulin, 2006), and ND-646, an allosteric inhibitor
of ACC, has also demonstrated antitumor efficacy in autochthonous mouse
lung tumor models (Svensson et al., 2016). Targeting FASN, which decreases
palmitoylation of tubulin and microtubule organization, decreases tumor cell
growth (Heuer et al., 2017; Luengo et al., 2017). TVB-2640 is the first com-
pound targeting FASN to enter clinical trials, and it has been reported that
combinatorial treatments with paclitaxel, can result in partial responses or pro-
longed stable disease (Brenner et al., 2017; Luengo et al., 2017).
Pharmacological inhibitors of enzymes catalyzing reactions in the de novo
pathways for biosynthesis of purine and pyrimidine nucleotides are synthetic
or natural-product analogues of pathway intermediates or, more recently,
inhibitors rationally designed from a knowledge of the catalytic mechanism
of action. These inhibitors are highly effective chemotherapeutic drugs.
These inhibitors show clinical efficacy not only against cancer, but also
against inflammatory disorders, or from infections. For human cancer, the
purine pathway is considered a better target for treatment strategies over
the pyrimidine pathway, since the inhibition of the later causes higher toxic
side effects (Lunt & Fendt, 2018). Drugs such as methotrexate and
6-mercaptopurine have multiple sites of action, which hampers the precise
prediction of their effects on cells. Recent studies utilize rational design of
inhibitors based on the X-ray structure of the target enzyme, and this leads to
the development of drugs with only one site of action in human cells.
VX-497 is an important example of such a product, which is a potent inhib-
itor of the purine enzyme, IMP dehydrogenase (Christopherson, Lyons, &
Wilson, 2002; Luengo et al., 2017).
A frequently used metabolic targeting drug is metformin, an antidiabetic
drug, that mimics caloric restriction acting on multiple levels of cell metab-
olism, reducing all energy-consuming processes in cells, including cell pro-
liferation (Luengo et al., 2017; Pierotti et al., 2013). As mentioned in the
above paragraphs, this drug is often used in combination with other chemo-
therapeutic agents for enhanced therapeutic action (Pierotti et al., 2013). In
addition, there are other metabolic strategies that target oncogenes and tumor
suppressor genes regulating cancer metabolism such as Ras, C-myc, HIF-1,
etc. (Iurlaro et al., 2014). Drugs/compounds targeting different proteins/
enzymes of the metabolic pathways are listed in Table 2 (Rahman &
Hasan, 2015). Chemotherapeutic targeting of cancer metabolism is a becom-
ing a robust field of research with significant clinical potential.
7.2 Ionizing radiation and metabolism

Ionizing radiation (IR) a known therapeutic strategy for treating patients with
cancer that can cause several acute and delayed changes in metabolic flux,
resulting in increased flux into glycolysis and pentose phosphate pathway for
detoxification of ROS (Sertorio et al., 2018; Yazal, Dao, Dong, Dratver, &
Vlashi, 2018). Altered activity of the enzymes PKM2 and G6PDH control
metabolic reprogramming as an acute response to radiation-generated oxida-
tive stress (Yazal et al., 2018). This helps re-balance the redox state of the sur-
viving cancer cells. PKM2 activators can be used to prevent these protective
metabolic rewirings and can significantly inhibit IR-induced cellular repro-
gramming of breast cancer cells (Yazal et al., 2018). In addition to glycolysis,
IR has been shown to affect other components of oncogenic metabolism. Such
as enhanced PPP signaling, increased FA biosynthesis, along with decreased
mitochondrial oxidative phosphorylation (Lee et al., 2017; Mims et al.,
2015). IR increases intracellular glucose, glucose 6-phosphate, fructose, and
products of pyruvate (lactate and alanine). IR also increases glycolysis by
upregulating GAPDH (a glycolysis enzyme), along with increasing lactate pro-
duction by activating LDHA, which is responsible for the conversion of pyru-
vate to lactate. LDHA inhibition prevents radiation-induced activation of
TGF-β ( Judge et al., 2015). In addition, lactate induces cell migration and
secretion of hyaluronan from cancer associated fibroblasts to support metastasis
(Hirschhaeuser, Sattler, & Mueller-Klieser, 2011). IR also increases MCT1
expression that exports lactate into the extracellular environment, leading to
acidification of the tumor microenvironment (Lee et al., 2017). These changes
result in IR-stimulated invasion of the non-irradiated, surrounding stromal
tissues and normal endothelial cells (Liao, Hsu, et al., 2014; Liao, Qian,
et al., 2014).
ROS plays a seminal role in the IR-induced glycolytic switch, possibly
though the regulation of Akt (Lee et al., 2017; Zhong et al., 2013). This is
supported by studies utilizing antioxidant SOD mimic treatment, which
suppresses IR-induced glucose uptake, prohibits the glycolytic switch,
and inhibits invasiveness (Lee et al., 2017; Zhong et al., 2013). IR-
induced ROS generation assists in the development of EMT and CSC
phenotypes through Snail, Dlx-2, HIF-1, and TGF-β. These molecules
can regulate the enzymes involved in glycolysis and mitochondrial oxidative
phosphorylation, causing the IR-induced glycolytic switch (Lee et al.,
2017). IR can also lead to elevated ROS generation via extracellular water
radiolysis and intracellular metabolic alterations or damage to mitochondria
(Lee et al., 2017). ROS is implicated in IR-induced HIF-1 activation which

stimulates vascular damage causing hypoxia that leads to stabilization by
Nijmegen breakage syndrome protein 1 (NBS1), and nuclear accumulation
(Harada, 2011; Harada et al., 2009; Kuo et al., 2015; Lee et al., 2017;
Moeller, Cao, Li, & Dewhirst, 2004; Rankin & Giaccia, 2016). IR-
induced glucose availability also facilitates HIF-1α translation by activating
the Akt/mTOR pathway (Harada et al., 2009). HIF-1α stabilized by IR can
dimerize with HIF-1β in the nucleus, regulating EMT molecules such as
Snail, which also controls cancer cell migration, and invasion (Luo, Wang,
Li, & Post, 2011; Rankin & Giaccia, 2016).
These studies predominantly document how radiation can upregulate can-
cer metabolism and thus contribute to resistance to radiotherapy. Targeting
the mechanism by which radiation upregulates cancer metabolism could rep-
resent a potential way of ameliorating this phenomenon. Radiation can also
lead to cytosolic nucleic acid sensing orchestrating tumor immunity during
radiotherapy (Deng et al., 2016). IR can thus use the host metabolism to result
in the upregulation of “find-me” and “eat-me” signals from tumor cells
(Fig. 7). These signals can be augmented further by appropriate immunother-
apy strategies to eradicate the tumor after radiation.
7.3 Targeting stromal cell metabolism for therapy

Cancer comprises a heterogeneous population of cells consisting of not only
cancer cells but also neighboring stromal cells, with a myriad of genetic and
epigenetic backgrounds. ROS decreases caveolin-1 expression in cancer
associated fibroblasts (CAFs) and this loss of caveolin-1 in CAFs causes fur-
ther increase in ROS production, leading to stabilization of HIF-1α which
promotes glycolysis in CAFs (Lee et al., 2017; Pavlides et al., 2009, 2010;
Sloan et al., 2009; Witkiewicz et al., 2009). CAFs altered this way take
up glucose and secrete lactate to “feed” adjacent cancer cells (Bonuccelli,
Tsirigos, et al., 2010; Bonuccelli, Whitaker-Menezes et al., 2010; Lee
et al., 2017; Lee & Yoon, 2015; Martinez-Outschoorn, Lisanti, & Sotgia,
2014; Martinez-Outschoorn, Sotgia, & Lisanti, 2014; Yoshida, 2015).
Epithelial cancer cells and CAFs express different subtypes of the lactate
transporter known as monocarboxylate transporter (MCT1 and MCT 4,
respectively) and this supports metabolic symbiosis required for adaptation
to changes in the nutrient microenvironment that is caused by cancer treat-
ment (; Lee et al., 2017; Lee & Yoon, 2015; Martinez-Outschoorn,
Lisanti, & Sotgia, 2014; Martinez-Outschoorn, Sotgia, & Lisanti, 2014;
Yoshida, 2015).
CAFs also demonstrate an upregulated glutamine anabolic pathway, pos-

sibly due to the metabolic pressure applied by cancer cells causing atypical car-
bon and nitrogen sources for glutamine synthesis (Yang et al., 2016). In support
of these observations, targeting stromal glutamine synthesis in an orthotopic
ovarian cancer model promoted tumor regression (Yang et al., 2016). T cell
metabolism in tumor stroma can also serve as attractive therapeutic targets,
to generate more effective adoptive cellular immunotherapies in cancer, and
to direct T cell differentiation and function toward non-pathogenic pheno-
types in settings of autoimmunity (O’Sullivan & Pearce, 2015).
8. Conclusion
Cancer metabolism plays a crucial role in every step of cancer, and
thereby provides promising targets for treating the individual components
and steps in the cancerous process. Moreover, targeting multiple compo-
nents in the metabolic process in heterogeneous and flexible (displaying plas-
ticity) tumors provides significant potential to treat cancer effectively. The
different metabolic pathways are interlinked, which adds a tight regulation
of the energetic process necessary for proliferating tumor cells under a vari-
ety of stressful situations. However, these requirements for energetic pro-
cesses can also serve as a cancer’s “Achilles Heel.” Impinging on one part
of the complex metabolic profile of a cancer cell may cause a collapse in
linked processes resulting in dysregulation of multiple connected metabolic
systems leading to cancer cell death. This makes understanding the nuances
of cancer metabolic reprogramming a very important and relevant area of
study (Fig. 15).
Radia on
Augmented with An oxidants
Immunotherapy
Glucose Lipid
Metabolism Metabolism
Inhibitors LKB1 NF-kB PI3K Inhibitors
HIF-1
AMPK CANCER Akt Targe ng

Nucleo de
Biosynthesis METABOLISM Stromal
Inhibitors mTOR C-myc Metabolism
p53 Ras Rb PTEN

Disrup on of An -
Proton Pump Oncometabolites
Serine Glutamine
Inhibitors Inhibitors
Fig. 15 Schema showing potential targets (shown in green) and targeting strategies
(red) that can disrupt cancer metabolism for therapeutic purposes.
9. Future prospects
Recent studies have used in silico modeling informed by proteomics to
predict metabolic changes in liver cancer, as well as identify metabolic targets
selective for cancer cells (Berndt et al., 2020; Frezza, 2020). Studies emphasiz-
ing the pH of cancer cells supports the concept of a “transport metabolon,” in
which multiple transporters collaborate to regulate the acid/base homoeostasis
in cancer cells, a key regulator of metabolism (Becker, 2020; Frezza, 2020).
Studies have even interconnected neurotransmitter serotonin signaling to affect
a proliferative advantage to breast cancer cells by both increasing cell prolifer-
ation and decreasing cell death (Frezza, 2020; Sola-Penna et al., 2020). Current
studies provide the evidence indicating that cancer metabolism is highly
dynamic and heterogeneous, and we need new analytical platforms to compre-
hend its full complexity. Further studies are necessary to analyze cancer metab-
olism at the single-cell level without disrupting tumor tissue. Metabolomic
analysis obtained by the destruction of the tumor tissue, do not provide a com-
plete picture of tumor heterogeneity. Studies where microdialysis is utilized to
study metabolic changes in brain tumors post cisplatin treatment, may permit
observation of distinct metabolic patterns associated with chemotherapy treat-
ment (Bj€ orkblom et al., 2020; Frezza, 2020). Some studies use technologies
such as matrix-assisted laser desorption and ionization imaging mass spectrom-
etry to investigate the distribution of phosphatidylinositols in human tumors
(Frezza, 2020; Kawashima et al., 2020). This work can help shape the future
direction of cancer metabolism analysis.
Using these and even newer state-of-the-art techniques may result in the
development of non-toxic inhibitors of metabolic pathways with profound
clinical efficacy. A myriad of metabolic targets are expected to be uncovered
and evaluated as putative targets for cancer therapy. New techniques to study
cancer metabolism are now merging with systems biology methodologies
and are further complemented by clinical metabolic profiling. These
approaches could provide improved strategies for cancer diagnosis and ways
of effectively measuring therapeutic efficacy.
Acknowledgments
The present study was supported in part by the National Foundation for Cancer Research
(NFCR) (P.B.F.), the Human and Molecular Genetics Development Fund (L.E., S.K.D.),
and the VCU Institute of Molecular Medicine (P.B.F.). P.B.F. is the Thelma Newmeyer
Corman Chair in Oncology in the VCU Massey Cancer Center.
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Metabolic Control of Cancer 2021

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CHAPTER THREE

Metabolic control of cancer

7. Metabolism and cancer therapy 147

1.1 Glucose metabolism

Metabolic symbiosis with CAFs

Ac vated in cancer Inac vated in cancer

Fig. 2 Relationship between glycolysis and oxidative phosphorylation in cancer cells.

dividing tumor cells. In addition, lactic acid secretion by the proliferating

member Mcl-1, pro-apoptotic BH3-only proteins (Puma, Bim, Noxa and

1.2 Lipid metabolism

lipid rafts to transduce intracellular cell signaling pathways (Fernández et al.,

In addition, MYC can also regulate mevalonate metabolism (Wang et al.,

1.3 Glutamine metabolism

1.4 Nucleic acid metabolism

1.5 One carbon metabolism

Fig. 8 (A) Cytosolic and mitochondrial compartmentalization of one-carbon metabo-

expression of these enzymes, even under serine-fed conditions. (Yang &

2. Metabolic heterogeneity between tumor types

3. Metabolic strategies engaged during tumorigenesis

4. Metabolic regulation of metastasis

4.1 Glucose metabolism in metastasis

cancer cell motility and invasion, as glycolysis generates the metabolic

Fig. 12 Metabolic rewiring supports cancer cell invasion by inducing signaling

Another mechanism by which glucose metabolism controls metastatic

4.2 Lipid metabolism in metastasis

metastasis. Internalization of fatty acids (FAs) is reported as a key aspect of

finger E-box binding homeobox 1 (ZEB1) signaling (Elia et al., 2018;

4.3 Epigenetic regulation of metastatic metabolic rewiring

nutritional condition of the cells. Diet-dependent changes in histone meth-

4.4 Regulation of EMT by oncogenic metabolism

In support of these findings, silencing of ACLY to suppress acetyl-CoA biosyn-

4.5 Metabolism of circulating cancer cells

to decrease glucose oxidation in breast cancer cells, reducing mitochondrial

5. Tumor-microenvironment and metabolic crosstalk

blood vessels, infiltrating inflammatory cells, a variety of associated tissue

5.1 Hypoxia and cancer cell metabolism

5.2 Metabolic coupling between tumor cells and stroma

(6-phosphofructo-2-kinase) in endothelial cells leads to decreased cancer

5.3 Metabolic preconditioning of the metastatic niche

6. Overlap in metabolic signatures of cancer cells

intermediates of central metabolic pathways function as key regulators of

6.1 Metabolic strategies used by cancer cells and pluripotent

the form of lactate to resist spontaneous differentiation or apoptosis

6.2 Metabolic regulation of chromatin and differentiation

6.3 Metabolic heterogeneity of cancer stem cells

Fig. 14 Metabolic regulation of epigenetic mechanisms. Metabolism and epigenetic

with increased dependence on mitochondrial function and oxidative phos-

7. Metabolism and cancer therapy

7.1 Chemotherapeutically targeting metastasis through

further metabolized in cells. This results in the competitive inhibition of

ACC knockdown resulted in apoptotic cell death in cancer cell lines

7.2 Ionizing radiation and metabolism

(Lee et al., 2017). ROS is implicated in IR-induced HIF-1 activation which

7.3 Targeting stromal cell metabolism for therapy

CAFs also demonstrate an upregulated glutamine anabolic pathway, pos-

AMPK CANCER Akt Targe ng

p53 Ras Rb PTEN

to promote metastasis. Nature Cell Biology, 17(2), 183–194. https://doi.org/10.1038/

Biological Chemistry, 284(8), 5332–5342. https://doi.org/10.1074/jbc.M806653200.

one-carbon unit fate. Nature Chemical Biology, 12(6), 452–458. https://doi.org/10.1038/

capacity of human melanoma xenografts. Science Advances, 3(11), eaao5268. https://doi.

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