Letter | Published:

Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer

Nature volume 527, pages 525530 (26 November 2015) | Download Citation


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 PDAC1,2,3,4. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like 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, 8, 9, 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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Gene expression microarray data have been deposited in the Gene Expression Omnibus under accession number GSE66981.


  1. 1.

    et al. Epithelial to mesenchymal transition: expression of the regulators snail, slug, and twist in pancreatic cancer. Clin. Cancer Res. 13, 4769–4776 (2007)

  2. 2.

    et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 69, 5820–5828 (2009)

  3. 3.

    et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc. Natl Acad. Sci. USA 107, 15449–15454 (2010)

  4. 4.

    et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012)

  5. 5.

    & The basics of epithelial–mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009)

  6. 6.

    , & Human correlates of provocative questions in pancreatic pathology. Adv. Anat. Pathol. 19, 351–362 (2012)

  7. 7.

    et al. Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression. J. Biol. Chem. 277, 39209–39216 (2002)

  8. 8.

    et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nature Cell Biol. 11, 1487–1495 (2009)

  9. 9.

    et al. Knockdown of snail sensitizes pancreatic cancer cells to chemotherapeutic agents and irradiation. Int. J. Mol. Sci. 11, 4891–4904 (2010)

  10. 10.

    , , , & Spatiotemporal regulation of epithelial–mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22, 725–736 (2012)

  11. 11.

    , , , & E-cadherin regulates cell growth by modulating proliferation-dependent β-catenin transcriptional activity. J. Cell Biol. 154, 1185–1196 (2001)

  12. 12.

    , & Dual role of transforming growth factor beta in mammary tumorigenesis and metastatic progression. Clin. Cancer Res. 11, 937s–943s (2005)

  13. 13.

    et al. Direct repression of MYB by ZEB1 suppresses proliferation and epithelial gene expression during epithelial-to-mesenchymal transition of breast cancer cells. Breast Cancer Res. 15, R113 (2013)

  14. 14.

    et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008)

  15. 15.

    et al. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc. Natl Acad. Sci. USA 107, 18115–18120 (2010)

  16. 16.

    et al. Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype. J. Cell. Physiol. 228, 556–562 (2013)

  17. 17.

    et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004)

  18. 18.

    et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131–1143 (2004)

  19. 19.

    et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann. Surg. Oncol. 14, 3629–3637 (2007)

  20. 20.

    et al. Expression of snail in pancreatic cancer promotes metastasis and chemoresistance. J. Surg. Res. 141, 196–203 (2007)

  21. 21.

    et al. Acquisition of epithelial–mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 69, 2400–2407 (2009)

  22. 22.

    et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin. Cancer Res. 21, 396–404 (2015)

  23. 23.

    et al. Stimulus-dependent differences in signalling regulate epithelial-mesenchymal plasticity and change the effects of drugs in breast cancer cell lines. Cell Commun. Signal. 13, 26 (2015)

  24. 24.

    et al. Epithelial–mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer. Ann. Surg. Oncol. 14, 3527–3533 (2007)

  25. 25.

    et al. Solitary cell infiltration is a novel indicator of poor prognosis and epithelial-mesenchymal transition in pancreatic cancer. Hum. Pathol. 41, 1061–1068 (2010)

  26. 26.

    et al. Pdx1 expression in pancreatic precursor lesions and neoplasms. Appl. Immunohistochem. Mol. Morphol. 19, 444–449 (2011)

  27. 27.

    et al. PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122, 983–995 (1996)

  28. 28.

    Pancreatic cancer. N. Engl. J. Med. 362, 1605–1617 (2010)

  29. 29.

    , & Smarter drugs emerging in pancreatic cancer therapy. Ann. Oncol. 25, 1260–1270 (2014)

  30. 30.

    , , , & Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation. J. Clin. Invest. 124, 338–352 (2014)

  31. 31.

    et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell 7, 469–483 (2005)

  32. 32.

    et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-β signaling in cooperation with active Kras expression. Genes Dev. 20, 3147–3160 (2006)

  33. 33.

    et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719–734 (2014)

  34. 34.

    et al. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep. 10, 1066–1081 (2015)

  35. 35.

    Limma: linear models for microarray data. In Bioinformatics and Computational Biology Solutions using R and Bioconductor (eds , , , & ) (Springer, 2005)

  36. 36.

    et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell 149, 656–670 (2012)

  37. 37.

    et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523, 177–182 (2015)

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We wish to thank D. Lundy, S. Yang, Z. Xiao, R. Deliz-Aguirre, T. Miyake and S. Lovisa for technical support and K. M. Ramirez and R. Jewell in the South Campus Flow Cytometry Core Laboratory of MD Anderson Cancer Center for flow cytometry cell sorting and analyses (partly supported by NCI grant no. P30CA16672). We also wish to thank E. Chang for scanning slides of histopathological specimens. This study was primarily supported by the Cancer Prevention and Research Institute of Texas. The research in the LeBleu laboratory is supported by UT MDACC Khalifa Bin Zayed Al Nahya Foundation.

Author information

Author notes

    • Xiaofeng Zheng
    •  & Julienne L. Carstens

    These authors contributed equally to this work


  1. Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA

    • Xiaofeng Zheng
    • , Julienne L. Carstens
    • , Jiha Kim
    • , Matthew Scheible
    • , Judith Kaye
    • , Hikaru Sugimoto
    • , Valerie S. LeBleu
    •  & Raghu Kalluri
  2. Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA

    • Chia-Chin Wu
  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Raghu Kalluri
  4. Department of Bioengineering, Rice University, Houston, Texas 77030, USA

    • Raghu Kalluri


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R.K. conceptually designed the strategy for this study and provided intellectual input. V.S.L. helped design experimental strategy, provided intellectual input, supervised the studies, performed immunohistochemistry and culture experiments, generated the figures and wrote the manuscript. X.Z. performed experiments to generate the genetically engineered mouse models and helped characterize the mouse phenotype, performed culture experiments, collected the tissue for analysis and contributed to the manuscript writing. J.L.C. characterized the mouse phenotype, analysed the data related to the genetically engineered mouse models, collected data, generated the figures and helped with manuscript writing and editing. H.S. performed experiments with mice and injected cancer cells and helped collect tissue, J.Ki., M.S., J.Ka., and C.-C.W. performed experiments and collected data. The data was analysed by J.L.C, V.S.L., X.Z., J.Ki, and C.-C.W.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Raghu Kalluri.

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