Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer

Maximilian Reichert, Basil Bakir, Leticia Moreira, Jason R. Pitarresi, Karin Feldmann, Lauren Simon, Kensuke Suzuki, Ravikanth Maddipati, Andrew D. Rhim, Anna M. Schlitter, Mark Kriegsmann, Wilko Weichert, Matthias Wirth, Kathleen Schuck, Günter Schneider, Dieter Saur, Albert B. Reynolds, Andres J. Klein-Szanto, Burcin Pehlivanoglu, Bahar MemisN. Volkan Adsay, Anil K. Rustgi

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The regulation of metastatic organotropism in pancreatic ductal a denocarcinoma (PDAC) remains poorly understood. We demonstrate, using multiple mouse models, that liver and lung metastatic organotropism is dependent upon p120catenin (p120ctn)-mediated epithelial identity. Mono-allelic p120ctn loss accelerates KrasG12D-driven pancreatic cancer formation and liver metastasis. Importantly, one p120ctn allele is sufficient for E-CADHERIN-mediated cell adhesion. By contrast, cells with bi-allelic p120ctn loss demonstrate marked lung organotropism; however, rescue with p120ctn isoform 1A restores liver metastasis. In a p120ctn-independent PDAC model, mosaic loss of E-CADHERIN expression reveals selective pressure for E-CADHERIN-positive liver metastasis and E-CADHERIN-negative lung metastasis. Furthermore, human PDAC and liver metastases support the premise that liver metastases exhibit predominantly epithelial characteristics. RNA-seq demonstrates differential induction of pathways associated with metastasis and epithelial-to-mesenchymal transition in p120ctn-deficient versus p120ctn-wild-type cells. Taken together, P120CTN and E-CADHERIN mediated epithelial plasticity is an addition to the conceptual framework underlying metastatic organotropism in pancreatic cancer. The functional basis of metastatic organotropism sheds light on the properties required for successful colonization of distant organs. Reichert et al. demonstrate that epithelial plasticity is a determinant of metastatic organotropism in pancreatic cancer with differing properties required for liver and lung colonization.

Original languageEnglish (US)
Pages (from-to)696-711.e8
JournalDevelopmental Cell
Volume45
Issue number6
DOIs
StatePublished - Jun 18 2018
Externally publishedYes

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Keywords

  • E-cadherin
  • epithelial plasticity
  • metastasis
  • organotropism
  • p120catenin
  • p120catenin isoform
  • pancreatic cancer

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

Cite this

Reichert, M., Bakir, B., Moreira, L., Pitarresi, J. R., Feldmann, K., Simon, L., Suzuki, K., Maddipati, R., Rhim, A. D., Schlitter, A. M., Kriegsmann, M., Weichert, W., Wirth, M., Schuck, K., Schneider, G., Saur, D., Reynolds, A. B., Klein-Szanto, A. J., Pehlivanoglu, B., ... Rustgi, A. K. (2018). Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer. Developmental Cell, 45(6), 696-711.e8. https://doi.org/10.1016/j.devcel.2018.05.025