PERSPECTIVES

On the complex route from the

VIEWPOINT
primary tumour to metastasis, cancer
cells need to adapt to permanently
EMT in cancer changing and often hostile environmental
conditions. This plasticity of tumour cells
is reflected by back-and-forth transitions
Thomas Brabletz, Raghu Kalluri, M. Angela Nieto and Robert A. Weinberg from differentiated to undifferentiated
or partial EMT-associated cancer cell
Abstract | Similar to embryonic development, changes in cell phenotypes defined
phenotypes4. EMT-TFs are crucial
as an epithelial to mesenchymal transition (EMT) have been shown to play a role in mediators of cellular plasticity, thereby
the tumorigenic process. Although the first description of EMT in cancer was in cell favouring progression to metastasis5,6.
cultures, evidence for its role in vivo is now widely reported but also actively An example of a prominent motor for
debated. Moreover, current research has exemplified just how complex this cell plasticity is the reciprocal feedback
phenomenon is in cancer, leaving many exciting, open questions for researchers loop between the EMT‑TF ZEB1 and
microRNA miR‑200 family members,
to answer in the future. With these points in mind, we asked four scientists for their which induce differentiation7. The observed
opinions on the role of EMT in cancer and the challenges faced by scientists plasticity, including the necessity to again
working in this fast-moving field. downregulate expression of EMT-TFs at
metastatic sites, indicates why despite their
What roles does EMT have in cancer However, besides activating classical oncogenic properties, EMT-TFs are rarely
biology? EMT-associated properties, an even more mutated in cancer.
important role of EMT-TFs in cancer The role of EMT-TFs in cancer is
Thomas Brabletz. Epithelial to biology is indicated by additional pleiotropic complicated by the fact that their additional
mesenchymal transition (EMT) is executed functions ascribed to EMT-TFs2,3. This functions are often non-redundant
by so‑called EMT-activating transcription makes it necessary to focus on the role of and tissue-specific. For instance, it was
factors (EMT-TFs), mainly of the SNAIL, EMT-TFs and not on the more restrictive demonstrated that SNAIL triggers metastasis
TWIST and ZEB families. EMT-TFs play term EMT. EMT-TFs have been shown in breast cancer 8, whereas it has no effect
important roles in all stages of cancer to maintain stemness properties and to on metastasis in a pancreatic cancer model9.
progression from initiation, primary increase tumorigenicity, linking them However, in contrast to SNAIL, ZEB1
tumour growth, invasion, dissemination to the concept of cancer stem cells (CSCs). favours metastasis in pancreatic cancer 10.
and metastasis to colonization as well as in Both features indicate why those factors Members of the same EMT‑TF family
resistance to therapy 1. Conflicting views already play a role in tumour initiation and can even have antagonistic functions,
about the role of EMT in cancer biology the formation of precursor lesions, which as shown in melanoma, where ZEB1 is
arose because the EMT is not a uniform cannot be explained by classical EMT tumour-promoting and ZEB2 reduces
programme defined by a single pathway and, features. Additionally, EMT-TFs are involved tumour aggressiveness11,12. Thus, it seems
secondly, because in addition to activating in double-strand DNA repair, the escape that activation of a classical EMT is the only
the ‘classical’ EMT, EMT-TFs have multiple from senescence and the induction of an common denominator of EMT-TFs, which
other functions. anti-apoptotic and pro-survival phenotype, have many specific additional functions.
Classical EMT, as first described in together resulting in an advantage under Another reason why the term EMT in cancer
embryonic development, results in the various types of stress conditions3. biology often causes confusion is the fact
transition of epithelial (E) cells to cells with Because oncogene-induced senescence that EMT-TFs are frequently expressed and
a mesenchymal (M) phenotype, defined by and apoptosis are fail-safe barriers against have profound effects in many non-epithelial
prototypical markers, such as E‑cadherin tumour progression, EMT-TFs support tumours. These include glioblastomas,
and vimentin. This programme is crucial malignant progression in addition to purely melanomas, different sarcoma types and
for many stages in embryonic development. stimulating cell motility. Moreover, these even leukaemia13.
Although reactivated in many cancer types, additional functions predispose EMT-TFs In summary, I am convinced that
it is rarely fully executed in tumour cells, to exert either intrinsic or acquired EMT-TFs play pleiotropic roles from
and end-stage markers such as vimentin are therapy resistance3. Additionally, EMT-TFs cancer initiation to metastasis, which
often not expressed. Nevertheless, a partial upregulate expression of pro-inflammatory is also reflected by their association
activation (partial EMT) by EMT-TFs and immunosuppressive cytokines in cancer with poor clinical outcome in many
increases cancer cell motility — both for cells, thereby triggering tumour-promoting epithelial tumour types and in non-epithelial
collective migration in cell clusters or as effects on the composition of the tumour tumour types. In addition to activating
individual cells — and thereby favours microenvironment (TME), including the classical EMT properties, EMT-TFs have
invasion and dissemination1. infiltrating immune system1. many non-redundant and tissue-specific

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 PERSPECTIVES

The contributors evidence for a 40% reduction in metastasis

was provided, leading to a conclusion that
Thomas Brabletz is Professor for Molecular Oncology and Chair of the Department of despite no evidence for compensation by
Experimental Medicine 1 in the Nikolaus-Fiebiger Center for Molecular Medicine at the University other EMT-TFs, some form of metastasis
of Erlangen-Nürnberg, Germany. His research is focused on mechanisms of tumour progression can occur without the requirement of a
towards metastasis and strategies to counteract it. He proposed the ‘migrating stem cell’ concept
ZEB1‑induced partial EMT programme10.
for metastasis, linking epithelial to mesenchymal transition (EMT) and stemness properties in
cancer cells, and currently investigates the role of EMT-activating transcription factors in cell By contrast, when SNAIL1 was deleted
plasticity, tumour initiation and malignant progression. in GEMMs mimicking breast cancer,
metastasis was reported as impaired, without
Raghu Kalluri is the R.E. Bob Smith Distinguished Chair of Cancer Research and Professor and
Chairman of the Department of Cancer Biology at the University of Texas MD Anderson Cancer any compensation by other TFs8. A different
Center and Director of the Metastasis Research Center, Houston, Texas, USA. His primary interests study that used complex GEMMs to probe
are extracellular matrix biology, tissue repair and regeneration, organ fibrosis and cancer biology. the acquisition of mesenchymal markers
M. Angela Nieto is CSIC Full Professor and former Head of Developmental Neurobiology at the of cancer cells demonstrated that cancer
Instituto de Neurociencias (Spanish National Research Council and University Miguel Hernández) cells in metastatic nodules did not exhibit
in Alicante, Spain. Her main interest is the study of cell plasticity and migration. In particular, she a partial EMT programme28, supporting
has studied the EMT for more than 20 years, both in embryonic development and in disease, and other, previous studies30–32. Collectively,
the effect that the reactivation of this developmental programme has in adult disease, including these studies suggest that metastasis
tumour progression, fibrosis and bone growth and mineralization. occurs without the requirement of a partial
Robert A. Weinberg’s research has focused on the molecular and genetic determinants of tumour EMT programme.
formation, beginning in the late 1970s with the mutant genes that work together to generate Therefore, at the moment, the case for
primary tumour cells. Over the past 15 years, his research has focused increasingly on the an absolute requirement of a partial EMT
non-genetic programmes that confer attributes of high-grade malignancy on primary tumour cells. programme for cancer metastasis is wide
open and requires an unbiased, rigorous
scientific effort. Our efforts must take into
functions. Therefore, in cancer biology EMT programme in cancer cells16–19. consideration that the function of a partial
dedifferentiation and cell plasticity are Interestingly, many investigators have EMT programme in cancer progression
more adequate terms than EMT, and the demonstrated that activation or suppression and metastasis may manifest differently in
usage of prototypical EMT markers (such as of any single EMT-inducing TF is sufficient distinct cancer types.
E‑cadherin and vimentin) as a simple way to induce an incomplete or partial EMT
to prove or exclude a role of EMT-TFs is programme without any compensation by M. Angela Nieto. I firmly believe that the
not appropriate. other EMT-inducing TFs18,19,23,24. Connected reactivation of developmental programmes
to the realization of the existence of a partial is at the centre of several adult diseases,
Raghu Kalluri. EMT was identified by EMT programme, it was demonstrated, including the EMT in cancer progression.
Betty Hay as important for vertebrate by employing an in vitro culture system, As such, the delamination of cells from
embryonic development 14. Subsequent work that cells with such a programme exhibited the primary tumour can occur through an
by many other researchers identified TFs, an improved ability for migration20,25. EMT-like process that may represent the
such as SNAIL1, TWIST1 and ZEB1, as key Eventually, by using mouse models, many first step in the metastatic cascade. However,
drivers of mesenchymal programmes during investigators suggested that the partial EMT the latter has been the subject of debate for
embryogenesis, and deletion of SNAIL1 programme of cancer cells was associated decades now, and therefore, I would like to
in mice results in embryonic lethality with with metastasis and chemoresistance2,26,27. comment on that before directly answering
impaired mesoderm development 15–19. Nevertheless, the question remained the question. In my opinion, the reason for
While it is generally accepted that during whether the partial EMT programme was this debate has several facets that can be
embryonic development, the EMT merely associated with improved metastasis summarized in three concepts: complexity,
programme leads to complete conversion or directly causal. plasticity and suboptimal experimental
of epithelial cells into mesenchymal cells, To address directly whether EMT-related models. The EMT is described as the
cancer cells in a tumour most often undergo TFs are responsible for chemoresistance, conversion of an epithelial (E) cell into a
an ‘incomplete’ or partial EMT20–22. This invasion and metastasis, the use of mesenchymal (M) cell, but the process is so
notion is not a newly discovered concept but genetically engineered mouse models complex that scientists in the field, including
was inherent to detection methods that were (GEMMs) to directly probe the function myself, have failed to stress the importance
used to identify a putative EMT programme of EMT-TFs was recently employed8–10,28,29. of the ‘T’. Indeed, ‘T’ stands for transition,
in cancer cells, namely, immunolabelling Genetic deletion of SNAIL1 and TWIST1 in implying the existence of transitioning
strategies. The cancer cells were identified pancreatic cancer GEMMs did not attenuate partial states. Importantly, some of these
as exhibiting an EMT programme when metastasis but conferred chemoresistance9. intermediate phenotypes can be the final
both epithelial and mesenchymal markers This work supported many studies that states in different contexts. As such, in
were detected in the same cancer cell, associated the partial EMT programme embryonic development, in fibrosis and
fulfilling the definition of an incomplete with acquisition of chemoresistance but also in cancer, there are good examples of
or partial EMT. Using a similar EMT did not support a direct role for SNAIL1 partial EMT states (see REF. 1 for a review).
detection system in the cancer cells, TFs, and TWIST1 in facilitating metastasis in The resulting cells fail to recapitulate all the
such as SNAIL1, SNAIL2, TWIST1 and pancreatic cancer 9. In a different study, characteristics of a bona fide mesenchymal
ZEB1, were identified as independently when ZEB1 was deleted in the context of cell described in textbooks but still represent
responsible for an incomplete or partial an identical GEMM of pancreatic cancer, EMT states. In addition, complexity also

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refers to the fact that EMT can be induced by
multiple extracellular signals that converge
in the activation of a plethora of EMT-TFs
that belong to different gene families.
Embryos activate slightly different EMT
programmes in different tissues and species,
resulting from the combination of the
EMT-TFs induced in a particular cell type
that translates into a particular morphology
and behaviour. This has a parallel in
tumours, as cancer cells in different tumour
types, and even within a single tumour,
are heterogeneous and express different
combinations of EMT-TFs. Thus, the
absence (either endogenous or after forced
silencing) of a specific EMT‑TF cannot be
taken as proof of the absence of EMT, and
the use of a particular mesenchymal marker
as a tool to follow EMT as a whole is not
appropriate33–35. This explains apparently
conflicting data, such as whether or not
EMT is important for the progression
of breast or pancreatic tumours to the
metastatic disease9,10,28,36, and points to
the existence of organ-specific EMT
programmes (discussed in REF. 37).
Another important issue to consider
when interpreting EMT data from animal
models is the dynamics of the process and
its plastic nature. Indeed, whereas EMT may
be important for cell delamination from
the primary tumour, it is not sufficient for
metastatic colonization. In other words,
invasive properties and metastatic potential
are not equivalent functional terms. It is
clear that without dissemination, metastases
would not develop, but even bearing
a high invasive potential, non-plastic
mesenchymal cells are unable to form
metastases29,30,38 as they need to recover
some epithelial characteristics to settle and
resume proliferation at metastatic sites.
This can explain why metastatic outgrowths
from carcinomas do not depict overt
mesenchymal properties, something that
has often been taken as an indication of the
absence of EMT. Rather, this can also be
interpreted as a result of the reversion of the
EMT to a more epithelial phenotype, similar
to that of the primary tumour.
Considering all the above, it is easy to
understand why it is so difficult to design
optimal animal models. Nevertheless,
current models are useful, provided the
complexity, dynamics and plasticity of
the process are taken into consideration
and the conclusions that can be reached are
not overestimated.
Finally, it is also crucial to understand
that both the embryonic and pathological
EMT programmes impinge not only on cell
morphology, invasion and motility but also
on stem cell-like properties, proliferation
and survival. This can explain why in
addition to dissemination, the EMT has been
found to be involved in other facets of cancer
progression, including tumour initiation
and chemoresistance (for examples, refer
to REFS 9,28,39).
Robert A. Weinberg. The contributions of
EMT programmes to cancer cell phenotypes
have been studied most intensively in the
context of carcinomas, although there is
clear evidence of notable contributions
of EMT to the biology of central and
peripheral nervous system tumours and
certain mesenchymal tumours (for example,
sarcomas). This raises the question of the
full spectrum of distinct cell-biological
phenotypes that the EMT orchestrates.
To begin, it is clear that the EMT
programmes operating in normal tissues
have considerable resemblance to those
operating in derived tumours. Indeed,
given existing evidence, it is plausible
that neoplastic cells adopt normal EMT
programmes, introducing only minor
changes into these programmes. This
realization, on its own, forces an interesting
conclusion: during the process of multistep
tumour progression of carcinomas, both
the beginning stage — involving fully
normal epithelial cells — and the final stage
— involving highly malignant carcinoma
cells — can express EMT programmes.
This essentially dictates that all the cell
populations between these two endpoints
can also express EMT programmes and
associated traits, including the ability to
disseminate. This notion, in turn, may
explain mechanistically the observations
that disseminated carcinoma cells can
already be observed at distant anatomical
sites relatively early in multistep primary
tumour progression.
While the EMT programme has long
been associated with the acquisition of
malignant cell traits, such as motility,
invasiveness and a heightened resistance to
various cytotoxic therapies, the discovery
almost a decade ago of the association
between the EMT programme and entrance
into stem cell programmes was hardly
anticipated. We now know that in certain
epithelial tissues, this association of EMT
and stemness operates in some normal
epithelial cells and the corresponding
derived neoplastic cells. Moreover, the
expression of the SLUG (also known as
SNAI2) EMT‑TF in normal mammary
epithelial cells (MECs) associates the
EMT programme with an entirely
normal physiological state rather than
the pathological states of wound healing
and neoplasia. Thus, shutdown of SLUG
in normal mouse MECs deprives them of
mammary gland-reconstituting activity,
indicating a causal role in the entrance
into and/or maintenance of the stem cell
state. Precisely how EMT programmes
facilitate the entrance of both normal and
neoplastic epithelial cells into stem cell states
remains elusive.
For cancer biologists, the greatest interest
in EMT programmes derives from their
association with the processes of invasion
and metastasis. These associations have by
now been extensively documented. Still,
there arises the question of causality: are
EMT programmes actually critical to the
display of these malignancy-associated
processes, or are they little more than
markers of these processes that play minor
functional roles in enabling their actions?
Definitive experimental proof that invasion
and metastasis can occur in the absence
of any involvement of EMT programmes
remains to be produced. In the case of
invasion, which in carcinomas typically
involves large, coherent, multicell phalanxes
of cells, the participating cells largely retain
associations with one another via adherens
junctions, testifying to their continued
expression of E‑cadherin and thus their
retained epithelial phenotype40. The key
players in these invasive cohorts appear to
be the carcinoma cells at the leading edges
of the invasive fronts. In some instances,
the activation of EMT-TFs, such as SNAIL,
has been documented in these cells41;
at the same time, these ‘leader’ cells retain
associations via adherens junctions with
the ‘follower’ cells moving close behind.
Definitive proof that an EMT programme
(or some of its component parts) is not
necessary for invasiveness would depend on
blocking this programme and demonstrating
continued invasion; such proof has not
yet been produced. A similar set of logical
issues is attached to the essentiality of EMT
in metastatic dissemination. In one recent
report, knocking out the master TF of the
EMT programme — ZEB1 — resulted in
a strong but still incomplete suppression
of metastatic ability 10. Other reports that
describe ongoing metastasis in the absence
of an EMT can be faulted because of their
inability to exclude the involvement of EMT
in primary tumour cells9,28,33,35.
While the essentiality of EMT in invasion
and metastasis still requires rigorous
examination and substantiation, there can

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be no question that the EMT programme
imparts to carcinoma cells many of the
attributes associated with the cells of
highly malignant tumours. This ‘guilt by
association’ provides a strong suggestion
that the EMT does indeed participate in
these processes, and, certainly, turning
on the EMT programme through the
induced expression of EMT-TFs leads to
great increases in the metastases formed by
otherwise weakly metastatic cells.
These findings lead in turn to yet another
question: how many of the steps of the
invasion–metastasis cascade, as defined by
Fidler 42, can be achieved by an activated
EMT programme? In this instance, the
implication is that activation of such a
programme in primary tumour cells can
orchestrate many of the steps of the cascade
without the concomitant need for mutations
in the genomes of the disseminating cells,
indicating that metastatic dissemination is
epigenetically templated and, in this sense,
does not depend on metastasis-promoting
somatic mutations arising within the primary
tumour cells. Given the known pleiotropic
actions of the EMT programme, it may
well convey cancer cells from the heart of
a primary carcinoma to the microvessels
of distant tissues, aid in their extravasation
and even facilitate the initial survival and
proliferation of the extravasated cells within
the tissue parenchyma. Nonetheless, it
appears unlikely that the actions of the EMT
programme can empower extravasated cells
to launch a programme of longer-term,
continuous proliferation, which appears
to depend on the adaptation of these cells to
foreign and potentially inhospitable tissue
microenvironments. This last step is plausibly
the least efficient in the invasion–metastasis
cascade and represents a high barrier to
successful colonization, the last step in this
multistep process.
Can all tumour cells undergo some
form of EMT?
T.B. In a conservative view, under the
definition of classical EMT, my answer is
“no”, because it would require an initial
epithelial phenotype and thus exclude
non-epithelial tumours. According to
the less restrictive view described above,
“some form of EMT” should include
EMT‑TF-dependent dedifferentiation and
plasticity. In this context, the question
would instead be “Do all tumour cells make
use of an EMT‑TF-induced programme?”
and my answer is “almost all, but to a
different extent”.
EMT-TFs can be activated in a vast
majority of tumour types, including
non-epithelial tumours13. Besides already
playing a potential role in tumour initiation,
they support tumour progression in different
ways. I proposed two extreme variants of
progression towards metastasis — a route
with phenotypic plasticity and a genetic
route43: differentiated cancers use the
plasticity programme and transiently activate
expression of EMT-TFs. Associated features,
such as cancer cell stemness, survival,
motility and so on, favour dissemination and
initial colonization. A downregulation of
EMT-TFs associated with redifferentiation
is necessary for metastatic outgrowth.
In this case, the vast majority of tumour
cells could be negative for EMT-TFs,
which may be detectable in only few cells
of the primary tumour and metastases.
In the second variant, primary tumours are
already irreversibly dedifferentiated, likely
owing to an increasing accumulation of
genetic alterations. Many tumour cells
of such undifferentiated, high-grade cancers
(for example, claudin-low breast cancers,
anaplastic thyroid cancer and glioblastomas)
express high levels of EMT-TFs. Such
tumours are very aggressive, therapy-
resistant and often highly metastatic,
without the necessity for phenotypic
plasticity. A mixture of both extreme
variants, dominated by one or the other in
individual tumours, is likely present in most
common human cancer types. Thus, in
my view, EMT-TFs, in one way or another,
play important roles in the majority of
human tumours.
Is there a way to progress towards
metastasis without any dedifferentiation
(EMT) or activation of EMT-TFs? This
question has been heavily discussed, and
accumulating data do not allow us to exclude
this view. For example, we described a
strongly reduced, but still present, metastatic
competence after ZEB1 depletion in a mouse
model of pancreatic cancer, where tumour
cells are ‘stuck’ in an epithelial phenotype10.
Those cancer cells used either strongly
reduced amounts of other remaining
EMT-TFs or a completely independent
mechanism to metastasize. Recently, in
an in vitro model system of squamous cell
carcinoma, it was shown that epithelial
tumour cells use tumour fibroblasts to
disseminate as epithelial–mesenchymal
couples44. This is an interesting mechanism,
and its relevance and abundance in human
cancers should be analysed.
In summary, I propose that in one
way or another, most human tumours
use EMT-TFs and associated properties,
but EMT‑TF-independent mechanisms of
cancer progression should be considered.
R.K. Many cell culture studies show
that most cells in a dish exhibit the
ability to undergo a full or partial EMT
programme18,20,45,46, but this situation does
not mimic real life. In human cancer tissue,
this question can be only partially answered
because we cannot perform genetic
fate-mapping or lineage-tracking of cancer
cells, and therefore, we have to depend on
subjective immunolabelling techniques.
Nevertheless, it is possible that ~5% of
tumour cells exhibit positive detection
of a marker suggestive of a partial EMT
programme9,47. Whether cancer cells exhibit
a wide spectrum of positive detection for
markers of the EMT programme remains
unanswered owing to the limitations
associated with the sensitivity of the
antibodies used and the imaging modalities
employed48,49. In many different mouse
models, fate-mapped transgenic models or
otherwise, it is clear that not all cancer cells
exhibit an EMT programme. Many studies
suggest that 5–10% of cancer cells exhibit
an EMT programme in mouse modelling
experiments9,28,47. Moreover, it is clear that
many cancer cells associated with metastatic
nodules do not show any evidence of a
previous history or current features of an
EMT programme9,28,30,50.
M.A.N. The simplest answer to this question
is that this has not been experimentally
addressed, but we know that this is not what
we observe in tumours, as not all cells in
the primary tumour change morphology
towards the mesenchymal state, nor do
they all express EMT-TFs. It is worth
mentioning here that the malignization of
tumour cells, understood as their ability to
disseminate, is not universal for all cells in
a tumour. If we now refer to the cells that
disseminate from the primary tumour, the
question is whether they can do it without
any signs of undergoing EMT. Alternative
modes of invasion and/or dissemination
have been described, including collective
migration, migration in cell clusters
or migration mediated by heterologous
cell–cell interactions44,51,52. Importantly,
this does not necessarily mean that by doing
so, cells are not deploying any of the EMT
subprogrammes, in particular during the
migration of cells in clusters. The latter is
surely an example of partial EMT52. Thus,
rather than engaging in a semantic issue,
it would be more appropriate to talk about

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cancer cell plasticity (alluding to changes
in cell phenotype from bona fide epithelial
to bona fide mesenchymal cells, including
their intermediate states). There is no doubt
that changes in cell behaviour towards the
motile state and intravasation and/or a break
from the primary tumour are required for
carcinoma cells to abandon the primary site
and eventually reach distant organs. Other
types of cell movements allow epithelial cells
to migrate as a collective sheet of cells, and
although relevant for some developmental
contexts and for local invasion, it is not
clear how those types of movement could
explain distant organ colonization or
even intravasation.
R.A.W. The EMT is a cell-biological
programme that is increasingly appreciated
to play a role in the physiology of all
epithelial tissues, doing so in embryogenesis,
wound healing and the formation of
neoplasias. Its involvement is therefore
plausible in all epithelia-derived tumours,
that is, carcinomas, and there are clear
indications that it also operates in at
least a subset of tumours of the central
nervous system (CNS), for example,
glioblastomas, which have an embryonic
origin in a primitive epithelium —
the neuroectoderm53. More recently, the
contributions of the EMT to the malignant
progression of neural crest tumours, such
as melanomas, have been observed54. The
involvement of the EMT programme in
these various neural tumours, including
the CNS and the peripheral neural crest
tumours, can be rationalized by noting
that the normal tissues from which these
tumours derive are epithelia of various types,
including the primitive neuroectoderm
and neural crest; indeed, in the case of
neural crest-derived tissues arising during
development, the transient activation of
an EMT programme is responsible for the
migration and dispersion of cells out of
the neural crest and the seeding of these cells
into the diverse array of tissues of neural
crest origin.
The role, if any, of the EMT in
the other two major tumour types —
haematopoietic and sarcomatous — is less
clear. Expression of the EMT-TFs, TWIST
and ZEB1 and/or ZEB2, has been linked
to more aggressive phenotypes of certain
leukaemias and lymphomas55,56; in these
instances, the traditional associations
of EMT with motility and invasiveness
are often not relevant to their biology. In
the case of sarcomatous tumours, higher
expression of EMT-TFs has been linked
to worse prognoses for sarcomas and
osteosarcomas57; in these latter cases,
analysis of EMT markers is complicated by
the fact that connective tissues normally
express an array of EMT-associated genes,
testifying to their origin in the mesoderm
as products of the first EMT — gastrulation.
To summarize, EMT programmes
participate in the pathogenesis of far more
tumours than was anticipated even a decade
ago, and many of the lessons learned from
study of the malignant progression of
carcinomas turned out to be applicable to
these diverse non-carcinomatous tumours.
Implicit in all these associations is the
notion that EMT programmes observed
in various neoplasias represent similar
programmes operating in the corresponding
normal tissues and cells‑of‑origin.
Unanswered by these surveys of tumour
types is the question of how many of
the discrete cell-biological phenotypes
associated with the EMT programme in
carcinoma cells are applicable to non-
carcinomatous tumours. In fact, traits
such as stemness, the formation of CSCs,
chemoresistance and invasiveness have been
documented in some of these cancers, but
documentation of their association with
EMT programmes is still quite rudimentary.
What are the major challenges and
future directions for investigators
working on EMT?
T.B. Because of their additional pleiotropic
functions in many tumour types, the focus
of future research should be EMT-TFs and
not classical EMT-associated features. This
would also reduce confusion concerning
this research area. However, research
in this area is challenged by the fact
that the different oncogenic functions
of EMT-TFs can be non-redundant and
tissue-specific and are often activated only
transiently and partially.
Future directions should therefore aim
to further characterize the roles of EMT-TFs
in normal tissue homeostasis and stem cell
biology and to understand the manipulation
of their (tissue-specific) physiological
functions in the context of accumulating
oncogenic mutations and the changing
TME. Experimental designs should include
in vivo methods, for example, applying
lineage-tracing and knockout techniques.
At the molecular level, the identification
of novel, specific cofactors will help us to
understand not only the specific functions
of EMT-TFs as transcriptional regulators
embedded in epigenetic complexes58 but
also their roles in additional processes,
as already exemplified for DNA repair.
A crucial topic is the investigation of
intracellular and extracellular networks,
which regulate and modulate the function
of EMT-TFs, like that already demonstrated
by feedback loops between EMT-TFs
and microRNAs or by functional links to
other pathways (for example, Notch and
WNT). In addition to the extracellular
stimuli of EMT-TFs, the identification
of tumour microenvironmental factors
counteracting their expression could help
our understanding of the re‑differentiation
of disseminated cancer (stem) cells
during colonization and metastasis. The
identification of interaction partners and
regulators will be the basis to identify
specific (functional) inhibitors of
EMT-TFs. Moreover, EMT-independent
and EMT‑TF‑independent mechanisms
of tumour progression and their
relevance for human cancers should be
further investigated.
Future research will not deliver a
simple answer. EMT-TFs are likely tumour
promoting in most tumour types, but they
may also be tumour suppressive in others
or even change their effects depending
on the stage of progression (for example,
dissemination versus colonization).
However, the pleiotropic functions of
EMT-TFs and the identification of their
specific effects in different human tumour
types and in different stages of progression
will also support the development of
therapeutic strategies to fight tumour
progression from initiation to metastasis.
R.K. The field of EMT research has been
evolving in the past 3 decades. It is now
clear that while cell culture studies provided
the initial impetus and excitement about the
potential causal role of the EMT programme
in cancer metastasis18,50,59,60, they might
have largely led to an overinterpretation
of the results. Studies using human cancer
tissue unequivocally demonstrated that
some cancer cells exhibit a partial EMT
programme, but the functional connection
to metastasis was at best an association.
Mouse models have been useful in
providing further insight into the weak
connection between the EMT programme
and metastasis. Some studies suggest
that an EMT programme is required for
metastasis, while other studies suggest that
an EMT programme is likely dispensable
for metastasis9,28. Therefore, more rigorous
and collaborative studies are required. One
major challenge in the field remains the

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availability of useful models to probe this
question carefully. Additionally, it is naive
to think that the requirement of an EMT
programme for metastasis is the guiding
principle for all cancers. Some cancers may
metastasize without the need for an EMT
programme, and others may depend on it,
and these differences must be unravelled
diligently and methodically without
dogmatic bias. One major challenge that
faces any research group is publishing data
that go against exciting concepts. Scientists
must be free to publish their independent
findings and allowed to arrive at their best
data-driven interpretations and let future
studies by the broader community and time
decide their true merit. Validation studies
are the best way to move science forward.
Exciting new technologies, such as dual
recombinase systems, tumour organoids and
inducible CRISPR–Cas9, are ushering in a
new era for EMT research. Added to this,
many researchers are embracing the notion
of team science and cross-validations of
research findings, which will undoubtedly
help move the field forward. Our patients are
counting on us to work together to unravel
the biology of metastasis and identify new
therapeutic targets.
M.A.N. In terms of basic research, the main
challenge is to be able to monitor all EMT
states and to follow all the cancer cells from
the primary tumour to the metastatic site
in improved animal models. This is not
trivial owing to the inherent complexity
and plasticity of the EMT programmes,
as mentioned above. Nevertheless, it
is crucial to understand the process to
be able to tackle the most important
challenges — for example, designing better
antimetastatic therapeutic strategies. To
do that, we need to select the best targets,
and rather than looking at the primary
tumours, we need to concentrate on the
biology at the metastatic niche. In patients,
dissemination from the primary site has
already occurred in the majority of cases
by the time of diagnosis, and we know that
the limiting step is metastatic colonization
and outgrowth. It is worth noting that we
have to be extremely careful when designing
antimetastatic strategies aimed at targeting
EMT. Due to the plasticity of cancer cells,
and the need for them to at least partially
revert to a more epithelial phenotype for
metastatic colonization, inhibiting EMT
(that is, the mesenchymal phenotype)
could favour epithelialization and, with that,
the formation of secondary tumours from
already disseminated mesenchymal tumour
cells. It would be desirable to be able to
selectively kill these disseminated cells, but
unfortunately, they are very much resistant
to cell death. Thus, it would be ideal to
specifically target their tumour-initiating
abilities, or in other words, their stem
cell-like properties.
R.A.W. The challenges to investigators are
present in multiple dimensions, as described
below. (i) Within an individual tumour, an
EMT programme may unfold to various
extents, depending on the location within a
tumour of the involved cells. (ii) EMT-TFs
collaborate in various combinations to
orchestrate EMT programmes. Because
they induce each other’s expression, and
because the different EMT-TFs elicit distinct
subsets of the traits associated with the
generic EMT programme, many versions
of EMT programmes may operate. (iii) The
EMT programmes may manifest in very
different ways in different tumours. Thus,
distinctive EMT-associated tissue-specific
gene expression programmes not associated
with the core EMT programme may be
found in some tissues but not in others.
(iv) A diverse array of extracellular signalling
pathways has been associated with EMT
induction in various normal and neoplastic
cell types. These pathways are triggered by
various contextual signals impinging on the
cancer cell surface and act combinatorially
to induce EMTs; moreover, the precise
molecular and biochemical connections
between many of these pathways and the
induction of EMT‑TF functions are still
poorly understood. (v) It is unclear how
many intermediate phenotypic states exist
between the fully epithelial and the fully
mesenchymal states at the two extreme
poles of the E-to-M spectrum. Associated
with this is the question of whether these
intermediate states can be plotted along a
single line or will eventually be represented
on a 2D map. (vi) Carcinoma cells appear
to maintain their residence in a metastable
manner over multiple cell generations in
some of these phenotypic states but only
transiently in others. The mechanisms
that ensure such metastable residence
remain elusive and may derive from the
multiple ways by which cells in general
achieve cell-heritable, multigenerational
transmission of phenotypes, including
stably inherited chromatin configurations
and positive-feedback, autocrine signalling
loops. (vii) It is unclear, at the level of
cell physiology, why and how the EMT
programme is associated with the
acquisition of stemness in both normal and
neoplastic tissues. While this association has
now been documented in various cell types
and tissues, its rationale remains unclear.
Specifically, why are these two programmes
(EMT and stemness) so intimately linked
in many adult cell types? (viii) In a variety
of commonly occurring tumour types,
it remains unclear what proportion of
resistance to both chemotherapies and
immunotherapies can be ascribed to the
actions of EMT programmes and what
proportion of resistance is acquired
through independent mechanistic routes.
(ix) While the central role of the EMT in
enabling metastatic dissemination has been
documented in diverse tumours, it is still
unclear whether all types of solid human
tumours depend on certain components
of the EMT programme in order to
metastasize. To date, demonstrations of
EMT-independent dissemination have
not proved to be definitive. (x) The cells
at the leading edge of invasive tumour
phalanxes exhibit EMT characteristics yet
retain physical associations with their more
epithelial-like followers. This raises the
question of whether an EMT programme
can be active in one subcellular sector of
an individual carcinoma cell but not in
another. (xi) While EMT programmes
favour the acquisition of carcinoma cell
stemness, yielding tumour-initiating cells,
it remains unclear why the robust outgrowth
of metastatic colonies seemingly founded by
more mesenchymal CSC pioneers depends
on the subsequent generation of flocks of
non-CSCs61. These non-CSCs appear to
collaborate with remaining CSCs that are
more mesenchymal in nature to fuel tumour
growth, but why and how they do so are
still obscure.
Thomas Brabletz is at the Department of Experimental
Medicine 1, Nikolaus-Fiebiger Center for Molecular
Medicine, FAU University Erlangen-Nürnberg,
Glückstr. 6, 91054 Erlangen, Germany.
thomas.brabletz@fau.de
Raghu Kalluri is at the Department of Cancer Biology,
Metastasis Research Center, University of Texas MD
Anderson Cancer Center, Houston, Texas 77054, USA.
rkalluri@mdanderson.org
M. Angela Nieto is at the Instituto de Neurociencias
CSIC-UMH, Avda. Ramón y Cajal s/n,
03550 San Juan de Alicante, Spain.
anieto@umh.es
Robert A. Weinberg is at the Whitehead Institute for
Biomedical Research, Ludwig Massachusetts Institute
for Technology (MIT) Center for Molecular Oncology
and MIT Department of Biology, Cambridge,
Massachusetts 02142, USA.
weinberg@wi.mit.edu
doi:10.1038/nrc.2017.118
Published online 12 Jan 2018

NATURE REVIEWS | CANCER VOLUME 18 | FEBRUARY 2018 | 133

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PERSPECTIVES

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Acknowledgements
R.K. thanks all the students, postdoctoral fellows and scien-
tists in his laboratory who contributed to the research on
EMT. Work in M.A.N.’s laboratory is funded by the European
Research Council (ERC AdG322694) and BFU2014-
53128-R. R.A.W. acknowledges funding received from the
Ludwig Center of Molecular Oncology and the Breast Cancer
Research Foundation.
Competing interests statement
T.B., R.K. and M.A.N. declare no competing financial inter-
ests. R.A.W. has an interest in and is on the scientific advisory
board for Verastem Inc.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.

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