Epithelial-to-Mesenchymal Transition is Dispensable for Metastasis but Induces Chemoresistance in Pancreatic Cancer
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Date
2015-11-26
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Publisher
Macmillan Publishers Limited
Abstract
Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is
associated with a dismal prognosis despite current best therapies;
therefore new treatment strategies are urgently required. Numerous
studies have suggested that epithelial-to-mesenchymal transition
(EMT) contributes to early-stage dissemination of cancer cells and
is pivotal for invasion and metastasis of PDAC1–4. EMT is associated
with phenotypic conversion of epithelial cells into mesenchymallike
cells in cell culture conditions, although such defined
mesenchymal conversion (with spindle-shaped morphology) of
epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes
occasionally observed in the tumour (partial EMT)5,6. Most studies
exploring the functional role of EMT in tumours have depended
on cell-culture-induced loss-of-function and gain-of-function
experiments involving EMT-inducing transcription factors such
as Twist, Snail and Zeb1 (refs 2,3,7–10). Therefore, the functional
contribution of EMT to invasion and metastasis remains unclear4,6,
and genetically engineered mouse models to address a causal
connection are lacking. Here we functionally probe the role of
EMT in PDAC by generating mouse models of PDAC with deletion
of Snail or Twist, two key transcription factors responsible for
EMT. EMT suppression in the primary tumour does not alter the
emergence of invasive PDAC, systemic dissemination or metastasis.
Suppression of EMT leads to an increase in cancer cell proliferation
with enhanced expression of nucleoside transporters in tumours,
contributing to enhanced sensitivity to gemcitabine treatment
and increased overall survival of mice. Collectively, our study
suggests that Snail- or Twist-induced EMT is not rate-limiting
for invasion and metastasis, but highlights the importance of
combining EMT inhibition with chemotherapy for the treatment
of pancreatic cancer.
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Citation
Zheng, X., Carstens, J. L., Kim, J., Scheible, M., Kaye, J., Sugimoto, H., ... & Kalluri, R. (2015). Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature, 527(7579), 525-530.