Genome Instability

and Mutation
Not all cancer cells are equal, they evolve in response to selective pressure driven by accumulation of mutations.
Cancer cells have to out-compete nearby cells for nutrients and other resources, avoid immune cell attack, and
suppress apoptotic self-destruction.
Due to the aberrant proliferation associated with cancer cells, there is an increased tendency of genomic changes
and mutations that contribute to the damage of multiple genes regulating cell division and tumor suppression. This
is known as genomic instability. Genomic instability has the tendency to compound in cancer cells, since survival-
enhancing mutations increase the probability that those mutations will propagate in future cells.
A mutation is an alteration of an organism’s DNA sequence. The nucleotides that compose our DNA can be added,
replaced, or deleted, and single- or double-stranded breaks can occur within the DNA strand. Complete sections of
DNA can also swap positions, be inadvertently replicated, or deleted. Most of these mutations are not cancer-related.
They can either be spontaneous or the result of environmental insults like chemicals and radiation. Despite the high
probability that such mutations can occur, our DNA is maintained relatively error-free. Our genome surveillance and
maintenance systems, mitotic checkpoints and DNA repair mechanisms are always working to mitigate common
daily factors that attempt to mutate our genetic code. A defect in any of these systems can increase the DNA’s
susceptibility to mutations, resulting in genomic instability and an increased risk of malignancy.
 ne such mechanism is the G2/M DNA damage checkpoint, which serves to prevent the cell from entering mitosis
O
(M-phase) with genomic DNA damage, facilitating genome surveillance and DNA repair. There are several key
proteins involved:
• D
 NA-dependent protein kinase (DNA-PK), a serine/threonine kinase complex composed of a heterodimer of
Ku proteins (Ku70/Ku80) and the catalytic subunit DNA-PKcs, is deployed to the site of double-stranded DNA
breaks almost instantly to initiate repair via non-homologous end joining.
• B RCA1 and BRCA2, two tumor suppressors that are found in breast and other tissue, contribute to DNA repair,
chromosomal stability and transcriptional regulation in response to DNA damage. Studies have shown that,
in response to DNA damage, BRCA1 is hyperphosphorylated and translocated to specific sites within the
replication fork. BRCA1 has also been shown to regulate the expression levels of several genes activated in
response to DNA damage. In addition, BRCA1 is required for the S-phase and G2/M-phase mitotic checkpoints.
BRCA2 plays a slightly different role than BRCA1 and is predominantly active in maintaining chromosomal
stability and mitotic recombination. Both BRCA1 and BRCA2 have been shown to repair double-stranded DNA
breaks via homologous recombination.
• C
 hk1 and Chk2 are key signaling transducers that are part of a complex network of gene integrity checkpoints,
damage detectors and tumor suppressors.
• p 53 is also known as the “guardian of the genome” for its role in conserving genomic stability. p53 plays a
central role in in a pathway that recognizes and mitigates oncogenic stress by halting proliferation and inducing
apoptosis/senescence in an attempt to allay accumulating DNA damage that could lead to malignancy. (Fun
fact, elephants have over 20 copies of the p53 gene to protect them from mutations.)
14
Aside from the genomic instability that arises from compounding DNA mutations, aberrant epigenetic modifications
can also dramatically change functional protein levels and affect genomic integrity. Two epigenetic mechanisms
that play an important role in genomic instability are DNA methylation and histone modifications. Hyper- and/or
hypomethylation of regulatory regions within genes can mimic DNA mutations and promote tumor progression. In
addition, the remodeling of chromatin structure via epigenetic modifications to histones can permit chromosomal
rearrangements that lead to chromosomal instability. Together, these epigenetic changes can also affect cell cycle
progression and checkpoint regulation, further contributing to genomic instability and cancer progression.

References:
1. Hanahan D, Weinberg RA (January 2000). “The Hallmarks of Cancer”. Cell. 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9
2. Hanahan D, Weinberg RA (March 2011). “Hallmarks of Cancer: the next generation”. Cell. 144 (5):646-74. doi: 10.1016/j.cell.2011.02.013.
3. Rogakou, E.P. et al. (1998) J Biol Chem 273, 5858-68.
4. Burma, S. et al. (2001) J Biol Chem 276, 42462-7.
5. Rogakou, E.P. et al. (1999) J Cell Biol 146, 905-16.

G2M/DNA Damage DNA Methylation DNA Methylation

Histone Marks
Contol Euchromatin
Maintenance Methylation During DNA Replication

Heterochromatin
UHRF1
Transcriptionally Inactive
Chromatin
Transcriptionally Active
Chromatin
UHRF1

DMAP1 DMAP1
HDAC2

NU PTF
Me
DNMT1 DNMT1

RF
NU PTF

B Me
Me
IR

RF
B Me
UV
PCNA
PCNA

Me Me

Critically Short FANCD2

Me
Telomeres CAF1 CAF1
POT1 TRF2 DNA Me

Repair n
Pericentric Heterochromatin tio

M
yla me on

eth 20m tion

Rad50

H ethy
NBS1

D
eth 4

yla
ti

4K la
DNA Repair

em
Mre11 M 3K yla

tio
H eth

M 1 hV

M 1 hV

M 1 hV

M 1 hV

n
SU

HP SU

SU

SU
Transcription Initiation

39

39

39

39
ATM/ (MRN) em

e
De novo Cytosine Methylation
ATR D

HP

HP

HP
e

e
HIPK2 DNA-PK
Caffeine TF
BRCA1
Methylation Methylation Me
Me
TSS Me
Me
Active Gene TET1/2/3 TF TF H3K9me H3K36me
BRCA1 Demethylation Demethylation
WIP1 c-Abl Rad51
MDM4 Nucleosome Depleted Region Pericentric Heterochromatin
Nuclear Export, Inactive X Chromosome
Ubiquitination MDM2 p53 Chk2 Rad52 Rb-Mediated Repression M
eth
H

m n
Chk1 3 yla

tio
Transcription Elongation
em K7 tio
D

yla

e
eth 9m n

eth

n
27

tio
Nucleolar HDAC1 HDAC1

PC C1

PC C1

PC C1

PC C1
Inactive Gene
14-3-3 yla e

M
cdc25A

PR

PR

PR

PR
p19Arf

yla
3K
Sequestration

eth
tio

H
M

M
or MDM2 DNMT3L DNMT3A/B DNMT3A/B DNMT3L TSS n

em
p53 Stabilization

D
TRIP12 p300/ cdc25A/C Me
p53 PCAF cdc25
Nuclear Exclusion Me

Ubiquitination
cdc25A/B Inactive Genes MBD1 MeCP2 MBD2/4 Me Me

WIP1 AurA
HDAC
Bora
PLK1 NuRD Complex Inactive X Chromosome
TopoII BRCA1 14-3-3σ Reprimo GADD45 p21Cip1 CDK7 SCF SETDB1 CoREST Sin3A HDAC Hox Gene Repression Anti-Silencing
HP1 MCAF MBD1 SUV39H1 MeCP2 MBD2/4 ATP
p90RSK TSS Methylation Degree: + Mono † Di ‡ Tri
Myt1
Nuclear H4K20me H3K9me H3K27me H3K4me H3K36me H3K79me
Exclusion Methylases: Methylases: Methylases: Methylases: Methylases: Methylases:
SCF SET8 / KMT5A (+) PRDM3 / KMT8E (+) Ezh2 / KMT6 (+,†,‡) MLL1 / KMT2A (+,†,‡) NSD1 / KMT3B (+,†) DOTIL / KMT4 (+,†,‡)
Tet-Mediated Cytosine Demethylation NSD1 / KMT3B (+,†) PPRDM16 / KMT8F (+) NSD2 / KMT3G (+,†,‡) MLL2 / KMT2B (+,†,‡) SMYD2 / KMT3C (+,†) Demethylases:
ASH1L / KMT2H (+,†,‡) G9a/EHMT2 / KMT1C (+,†) NSD3 / KMT3F (†,‡) MLL3 / KMT2C (+) NSD2 / KMT3G (+,†) ???
Wee1 Ubiquitination Cytosine SUV420H1 / KMT5B (†,‡) EHMT1 / KMT1D (+,†) Demethylases: MLL4 / KMT2D (+) SET2 / KMT3A (‡)
DNMT BER ASH1L / KMT2H (+,†,‡) JHDM1D / KDM7A (+,†) SET1A / KMT2F (+,†,‡)
cdc2 Key SUV420H2 / KMT5C (†,‡) Demethylases:
NSD2 / KMT3G (+,†) PRDM2 / KMT8A (+,†,‡) PHF8 / KDM7B (+,†) SET1B / KMT2G (+,†,‡) JMJD1A / KDM2A (+,†)
—Cytosine
SE Cyclin B M-P Demethylases: PRDM8 / KMT8D (†) UTX / KDM6A (†,‡) NSD3 / KMT3F (+,†) JMJD1B / KDM2B (+,†)
PH A
5-Methylcytosine
H ASE —Methylcytosine JMJD3 / KDM6B (†,‡) NSD2 / KMT3G (+,†) JMJD2A / KDM4A (†,‡)
G2 -
JHDM1D / KDM7A (+,†) SUV39H1 / KMT1A (†,‡)
—5-Hydroxy PHF8 / KDM7B (+,†) SUV39H2/ KMT1B (†,‡) SET7 / KMT7 (†) JMJD2B / KDM4B (†,‡)
Methylcytosine Tet 1/2/3 TDG ESET / KMT1E (†,‡) SMYD3 / KMT3E (†,‡) JMJD2C / KDM4C (†,‡)
—H3K9me3 CLLD8 / KMT1F (†,‡) ASH1L / KMT2H (+,†,‡) JMJD2D / KDM4D (†,‡)
5-Hydroxy Demethylases: PRDM9 / KMT8B (‡) KDM4DL / KDM4E (†,‡)
—H3K4me0 Methylcytosine 5-Carboxycytosine
AOF1 / KDM1B (+,†) Demethylases:
—H3K36me3 JMJD1A / KDM3A (+,†) LSD1 / KDM1A (+,†)
—H3K27 Acetyl Tet 1/2/3 Tet 1/2/3 JMJD1B / KDM3B (+,†) AOF1 / KDM1B (+,†)
5-Formylcytosine JMJD1C / KDM3C (+,†) JARID1A / KDM5A (†,‡)
JHDM1D / KDM7A (+,†) JARID1B / KDM5B (†,‡)
PHF8 / KDM7B (+,†) JARID1C / KDM5C (†,‡)
JMJD2A / KDM4B (†,‡) JARID1D / KDM5D (†,‡)
JMJD2B / KDM4B (†,‡)
JMJD2C / KDM4C (†,‡)
rev. 06/14/18 JMJD2D / KDM4D (†,‡)
KDM4E / KDM4DL (†,‡)

“Due to the aberrant proliferation

associated with cancer cells,
there is an increased tendency of
genomic changes and mutations
that contribute to the damage of
multiple genes regulating cell
division and tumor suppression.”

visit www.cellsignal.com/pathways to see all pathways 15

 Tumor-promoting
Inflammation
Cancer cells hijack inflammatory mechanisms to promote their own growth and survival. During a normal inflammatory
response by the innate and adaptive immune system, immune cells carry out their designated task of engulfing and/or
destroying foreign invaders.
Within the complex tumor microenvironment, the same infection-fighting immune cells are corrupted by cancer cells. As
a result, instead of destroying the transformed cells, the anti-tumor immune cells are subverted into tumor-promoting
immune cells that secrete pro-survival, pro-migration, and anti-detection factors that allow tumor growth and metastasis.
Important molecules and signaling pathways in mediating the immune response to the tumor microenvironment include
NF-κB, inflammasome signaling, tumor-infiltrating immune cell markers, and immune checkpoint signaling.
NF-κB
In immune cells, NF-κB signaling regulates the transcription of genes, influencing innate and adaptive immunity,
inflammation, stress responses, B-cell development, and cytokine/chemokine release. In unstimulated cells, NF-κB is in
a complex with IκB inhibitory proteins in the cytoplasm. Upon activation, IκB proteins are phosphorylated, then targeted
for rapid degradation through the ubiquitin-proteasome system. Removal of IκB proteins releases the sequestered NF-κB,
allowing its entry into the nucleus where it can regulate gene expression.
NF-κB signaling in cancer and immune cells within the tumor microenvironment has been particularly implicated in the
epithelial-to-mesenchymal transition (EMT) of cells on the tumor border, allowing the detachment and migration of the
tumor mass. EMT is a classic hallmark of malignant cancers. Thus, the cross talk between NF-κB signaling in immune-
infiltrating cells and cancer cells establishes an environment that promotes tumor growth, invasion, and malignancy in
cyclical feedforward manner.
Inflammasome Signaling
The innate immune system is the first line of defense in protection from pathogenic microbes and host-derived signals of
cellular distress. One way in which these “danger” signals trigger inflammation is through activation of inflammasomes,
which are multiprotein complexes that assemble in the cytosol. The inflammasome promotes the cleavage of caspase-1
and subsequent cleavage of proinflammatory cytokines IL-1β and IL-18. The best characterized inflammasome complex
is the NLRP3 complex, which contains NLRP3, ASC (an adaptor protein) and a number of other proteins.
Tumor-infiltrating Markers
The immune system can identify and eliminate cancer cells through both innate and adaptive mechanisms; however,
such antitumor responses can be inhibited by the microenvironment through a process known as immunosuppression.
Cancer immunotherapy aims to manipulate both immunosuppressive and immunostimulatory mechanisms to increase
the anticancer immune response. Therefore, it is important to understand tumor-infiltrating immune cells and their role in
tumor growth and suppression.
Tumor-infiltrating immune cells are derived from either a myeloid or lymphoid cell lineage. The abundance and subtype of
immune cells within a tumor microenvironment correlate with prognosis. In addition, careful analysis of these two origins can
lead to the development of suitable immunotherapeutic strategies for patients.

16
Once a tumor is established, it can circumvent immune detection through various mechanisms including antigen loss,
down-regulation of major histocompatibility molecules, alteration of the endogenous antigen presentation pathways, and
immune suppression via cytokine secretion. Along with their ability to evade detection by the immune system, tumors
can also hijack immune cells to promote self-growth and metastasis. Immune suppression and subversion by a tumor
generally occur in a step-wise manner.
Immune Checkpoints
Immune checkpoints refer to the built-in control mechanisms of the immune system that maintain self-tolerance and
help to avoid collateral damage during a physiological immune response. Research has shown that tumors engineer
microenvironments to evade immune surveillance and attack, particularly by modulating certain immune checkpoint
pathways3.
Because T cells are the primary effector immune cells, they express multiple autoinhibitory cell surface receptors, such
as lymphocyte-activation gene 3 (LAG-3), programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated
protein 4 (CTLA-4), that modulate their response. Within the tumor microenvironment, tumor cells can upregulate the
ligands to these receptors to enhance tumor tolerance and evade eradication by the immune system.
In recent years, pharmacological modulators of these ligand-receptor interactions, known as immune checkpoint
therapies, have been intensely researched and deployed as novel immunotherapy agents to treat cancers. Of particular
interest are monoclonal antibodies against PD-1 and CTLA-4. Given the early success of these immune checkpoint
therapies in activating anti-tumor immune responses, creating immunotherapies targeting other co-inhibitory and co-
stimulatory receptors and their ligands in order appears to be a compelling therapeutic strategy.
Learn more about the pathways and proteins involved in Tumor-promoting Inflammation:
• NF-κB Signaling
• Inflammasome Signaling
• Tumor-infiltrating Markers
• Immune Checkpoints in the TME

References
1. Hanahan D, Weinberg RA (January 2000). “The Hallmarks of Cancer”. Cell. 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9
2. Hanahan D, Weinberg RA (March 2011). “Hallmarks of Cancer: the next generation”. Cell. 144 (5):646-74. doi: 10.1016/j.cell.2011.02.013.
3. Sharma P, Allison JP. The future of immune checkpoint therapy. 2015;348(6230):56-61

Nf-κB Signaling Inflammasome Signaling

Signal 1 Signal 2
Tummor-infiltrating
Markers
inflammasome activators are indicated in green

TNF Growth Factors: Crystaline Substances PAMPs/DAMPs Flagellin

IL-1 BMP, EGF, HGH, (alum, uric acid, silica) pore-forming toxins Type III
Insulin, NGF, TGF-α TNF-α ATP Cholesterol Crystals virus, bacteria, fungi
LPS, CpG,
ssRNA, dsRNA
LT, CD40L, secretion Non
Ag-MHC LPS
IL-1R TNFR BAFF/BLys Amyloid-β Anthrax system canonical
Ag dsDNA Tumor-Infiltrating Immune Cell Marker Guide (Human)
TCR TLRs GF-Rs toxin Gram-
LTβR, P2X7 negative
ub MyD88 TRADD CD40,
BCR
ub ub TNFR bacteria Leukocytes
IRAK1/4 ubc13 Ras BR3
c-IAP1/2 TRAF2/5 TLR4
Pellino TRAF2/6 TRAF2
CD45+
For detailed signaling, TRAF3
RIP TRAF
see TLR Pathway. lysosomal
For detailed signaling, ub c-IAP1/2 MyD88 AIM2
Ubc13 PI3K TRIF damage
Myeloid Cells Lymphoid Cells
see BCR Pathway. A20
Class

TRAF6 ASC LPS

K+ efflux ROS pro-caspase-1 CD11b+
For detailed signaling, UEV1A ITCH TAX1BP1
ub PDK1
see TCR Pathway. ub
RNF11 CYLD pro-mCasp-11/ Myeloid-Derived Plasmacytoid Conventional
pro-hCasp-4,5 Granulocytes Macrophages Monocytes T Cells NKT Cells NK Cells B Cells Plasma Cells
TRAF6 TAB1/2
Supressor Cells (MDSCs) Dendritic Cells Dendritic Cells
Cell Type

Stress: ROIs, Akt Siglec-H and

+
CD11c and
+
CD68 and
+
CD14 and
+
CD3+ CD56+and CD56+and CD19+ BCMA+or
TAK1 NIK Cathepsins CD317+ HLA-DR+ HLA-DR+and HLA-DR+and CD3+ CD3 – CD138+
UV, metals, Cot Naïve
LUBAC NLRP1
Activated CD11c – CD206–and
IgD+and
ischemia, shear ELKS CD86–
CD27 –
HOIL1 HOIP Tax ASC pro-caspase-1 mCasp-11/ Neutrophils Monocytic CD83+ CD1c+ M1-like Helper Type I PB Cytotoxic

IKKβ IKKα ub β-TrCP IKKα IKKβ NEK7 hCasp-4,5 CD16+and (M) MDSCs DCs CD86+or T Cells (Th) NKT (iNKT) NK Cells Switched
ub CD66b+or CD15–and CD1c+ CD80+or CD4+ TCR Vα24 Vβ11+ CD56 low and Memory
SHARPIN IKKγ/ NEMO NLRP3 CD15/SSEA1+ CD14+and iNOS+ CD16+ IgD –and
NEMO HLA-DR – CD1c–and Th1 Type II Cytotoxic CD27+
ub IKKα IKKα Mitochondria Eosinophils CD141–or M2-like T-Bet+ NKT
ub ub Granzyme+
β-TrCP • mtDNA Gasdermin D CD193+and
Siglec-8+and
Polymorphonuclear
(PMN) MDSCs
CLEC9A–
DCs
CD163+or
CD206+
Th2 or Perforin+
Unswitched
IgD+and
• mtROS cleavage CD16 – CD15+and CD1c –and
GATA-3+
JNK
CD27+
CD14–and CD141– or Th17 PB Immature
ub ub • NLRP3 NAIPs NLRC4
p65/ ASC Basophils HLA-DR – CLEC9A – or RORγt+ / Regulatory

CK2 Proteasomal localization FcεR1α+and NK Cells

RelA/cRel IκBα/β/ε
XCR1–
IκBα RelA ASC pro-caspase-1 Treg
Subtypes

Degradation CD117 – CD56 high and

NF-κB2 RelB
FoxP3+and
NF-κB2 • cardiolipin Activated
CD141+or
CD16 –and
p38 NF-κB1 p52 ub p100 CD63+and
CLEC9A+ CD25+
NCR+
p50 IKKα/β/ε Genotoxic
DCs
UV autophagy
CD203c+ (excel at cross- Cytotoxic Activated

Stress pro-caspase-1 presentation) T Cells

PKCζ CD141+or CD69+
NAP1 NAK GSK-3β IκBα Mast cells CLEC9A+or
CD8+
FcεR1α+and XCR1+
Nuclear-cytoplasmic CD117+and
Activated Cytotoxic Naïve Effector Memory

shuttling of non- MSK1 p65/RelA TXNIP NLRP3

Activated CD69+or Granzyme+ CD45RA+and CD45RO+and
RSK1 Proteasomal
NF-κB
Tryptase+
or CD62L+or CCR7+ CD62L–or CCR7 –
Key
phosphorylated forms Processing
CD25+ Perforin+
Ca2+
+
inflammasome
CD83+ positive / high expression
Activated
p65/
–
Central Memory Effector Exhausted negative /low expression

PKA C RelA CK2

CD203c+
ub K63-ubiquitin IKKγ/ CD45RO+and CD45RA+and PD-1+and TIM-3+
Functional State Markers
ub CYLD NEMO NLRP3 Inflammasome pyroptosis CD62L+or CCR7+ CD62L–or CCR7 – and LAG3+
NF-κB
ub K48-ubiquitin p50/52 IKKα IKKα inflammasome Complex
Bcl-3 Tumor-Infiltrating Immune Cell Marker Guide (Mouse) rev. 12/19/18
RelB IκBα complex
IκBζ NF-κB2
p52
Leukocytes
m
Cytoplas
PCAF SUMO cleavage CD45+

IKKγ/
Nucleus NF-κB p65/ ac CBP/ NEMO IKKα IKKα
p50/52 RelA p300 Gasdermin pyroptosis Myeloid Cells Lymphoid Cells
Class

RelA/cRel IκBα/ε NF-κB NF-κB NF-κB2 RelB

CD11b+
SUMO
NF-κB1 p50/52 p50/52 p52 caspase-1 eicosanoid vasodilation
p50 Myeloid-Derived Plasmacytoid Conventional
H3 synthesis hemoconcentration Granulocytes Macrophages Monocytes T Cells NKT Cells NK Cells B Cells Plasma Cells
HDAC Supressor Cells (MDSCs) Dendritic Cells Dendritic Cells
Cell Type

PIASγ ATM PARP1 Siglec-H+and CD11c+and F4/80 high CD14+and CD3+ CD3+and NK1.1+or CD19+ BCMA+or
NOX2 phagosome maturation CD317+ MHCII + F4/80 – NK1.1+ NKp46+or Naïve CD138+
Survival, Proliferation, Inflammation, Immune Regulation Lymphogenesis, B Cell Maturation us
Activated NKG2D+and
IgD+and
cle CD3 –
Nu glycolytic enzymes metabolism Neutrophils Monocytic CD83+ XCR1/ M1-like Helper Type I Activated
CD27 –
F4/80 med and (M) MDSCs CLEC9A+ CD86+or T Cells (Th) NKT (iNKT) Switched
Ly-6G+ Ly6C+and DCs CD80+or CD4+ TCR Vα14-Jα18+ CD69+ Memory
p65/RelA NLRP3 Ly6G–and (excel at cross- iNOS+ IgD –and
NF-κB Eosinophils Arginase+ presentation) Th1 Type II Cytotoxic
pro-IL-1β IL-1β XCR1+or CD27+
CD193+and M2-like T-Bet+ NKT
inflammation F4/80 med and Polymorphonuclear CLEC9A+ CD163+or Th2
Granzyme+
or Perforin+
Unswitched
pro-IL-18 IL-18 Siglec-F+ (PMN) MDSCs
CD8α+
CD206+or GATA-3+ IgD+and
Ly6C lowand Arginase+ CD27+
Basophils Resident
Ly6G+and Th17
FcεR1α+and DCs RORγt+
Arginase+
CD117 – CD8α+
Treg
FoxP3+and
Subtypes

Mast cells CD103+

FcεR1α+and Migratory CD25+
CD117+and DCs
CD23 CD103+ Cytotoxic
T Cells
CD11b+ CD8+
DCs
Activated Cytotoxic Naïve Effector Memory
CD11b+and Key
CD8α –and CD69+or Granzyme+ CD44–and IL7Rα+and +
or Perforin+ CD44+and CD62L– positive / medium / high
CD103 –or CD25+ CD62L+
expression
XCR1 –or –
negative / low expression
Central Memory Effector Exhausted
Activated CLEC9A –
IL7Rα+and CD44+and PD-1+and TIM-3+
Functional State Markers
CD83+ CD44+and CD62L+ CD62L– and LAG3+

rev. 12/19/18

visit www.cellsignal.com/pathways to see all pathways 17

 Activating Invasion
and Metastasis
Tissue invasion is the mechanism by which tumor cells expand into nearby environments. Metastasis refers to the
process of tumor cells breaking away from the primary tumor, migrating to a new location and establishing a new, or
secondary tumor, in the new environment. Both of these complex processes leverage existing cellular mechanisms,
such as the Adherens Junction Signaling pathway, to enable invasion and migration of the tumor cells.
Adherens junctions are dynamic structures that form, strengthen and spread, degrade, and then re-form as
their associated proteins create connections with counterparts from adjacent cells. The Adherens junction
serves multiple functions, such as initiation and stabilization of cell-cell adhesion, regulation of the actin
cytoskeleton, intracellular signaling, and transcriptional regulation. They can appear as bands encircling the cell
(zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques).
Under normal conditions, this helps create order among the cells. Cell-cell junctions link cells to adjacent cells
in tissue. They also regulate tissue homeostasis in critical cell processes that include tissue barrier function, cell
proliferation, and migration. Defects in cell-cell junctions give rise to a wide range of tissue abnormalities that disrupt
homeostasis and are common in genetic abnormalities and cancers.
The connection between cell junctions and the cytoskeleton is still under investigation. It may be more dynamic than
originally considered and may rely on multiple, weak associations between the cadherin-catenin complex and the
actin cytoskeleton or rely on other membrane-associated proteins.

Learn more about Adherens Junction Signaling and the proteins involved.

References
1. Hanahan D, Weinberg RA (January 2000). “The Hallmarks of Cancer”. Cell. 100 (1): 57–70. doi:10.1016/S0092-8674(00)81683-9
2. Hanahan D, Weinberg RA (March 2011). “Hallmarks of Cancer: the next generation”. Cell. 144 (5):646-74. doi: 10.1016/j.cell.2011.02.013.
3. G
 arcia, Miguel A. (April 2018). “Cell-Cell Junctions Organize Structural and Signaling Networks to Regulate Epithelial Tissue Homeostasis”. Cold
Spring Harb Perspect Biol. 2; 10(4): a029181.
4. H
 artstock A, Nelson WJ (March 2008). “Adherens and Tight Junctions: Structure, Function and Connections to the Actin Cytoskeleton”. Biochim
Biophys Acta. 1778(3): 660–669.

Adherens Junction
Signaling
Cytoplasm

Nectin
Maintenance
Extracellular
Space Disassembly
Formation
Cadherin PTPµ
Nectin
Cadherin

δ-cat Rac
Fyn Gβ1 δ-cat δ-cat
Clathrin
p190 RhoA IQGAP
α-cat β-cat Afadin Afadin
δ-cat β-cat Caveolin
SH2D1A Vinculin α-cat Ub UbUb
Cytoplasm c-Cbl E3
β-cat Tiam1
α-cat Vin β-cat
cu LAMTOR1 γ-cat
lin
Rac PRK1 Rac Formin WASP
Par3/6 aPKC α-cat Axin1
PI3K CK2 Ajuba
RhoA
Actin bundles Cip4
ARHGAP1
IQGAP
Src
δ-cat PTP1B
Akt α α
Ect2 Cortactin
cdc42 mDIA
β-cat α-cat
IQGAP α α-actinin
Centralspindlin
ndocytosis

Complex WASP IRSp53 • Anti-Apoptotic Signals APC

• Apoptosis
Adherens Arp2/3 Arp2/3 Actin
• Angiogenesis
Junction Disassembly
GSK-3
E

Remodeling
herin

β-cat
Src
Cad

α-cat β-cat
• Actin Nucleation ROCK Cadherin APC
RaIA
• Actin Dynamics Recycling Ub

VE-Cadherin Rap1 β-cat

Ub
Ub
Occludin Ub
β-cat
δ-cat
MLC
Increased Wnt Cadherin
Actomycin Signaling Degradation
Kaiso
Contractility β-cat
LEF/TCF
Caveolin/Clathrin β-catenin
Cytoplasm Nucleus Cell Growth & Differentiation Phagosome Degradation

18 visit www.cellsignal.com/pathways to see all pathways

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6
5

10

8 9

Images made using using our IHC-validated recombinant monoclonal antibodies.

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