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Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer.

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.

SUBMITTER: Reichert M

PROVIDER: S-EPMC6011231 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer.

Reichert Maximilian M Bakir Basil B Moreira Leticia L Pitarresi Jason R JR Feldmann Karin K Simon Lauren L Suzuki Kensuke K Maddipati Ravikanth R Rhim Andrew D AD Schlitter Anna M AM Kriegsmann Mark M Weichert Wilko W Wirth Matthias M Schuck Kathleen K Schneider Günter G Saur Dieter D Reynolds Albert B AB Klein-Szanto Andres J AJ Pehlivanoglu Burcin B Memis Bahar B Adsay N Volkan NV Rustgi Anil K AK

Developmental cell 20180601 6

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 Kras<sup>G12D</sup>-driven pancreatic cancer formation and liver metastasis. Importantly, one p120ctn allele is sufficient for E-CADHERIN-mediated cell adhesion. By contrast, cells with bi ...[more]

PMID: 29920275

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Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer.

Publications

Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer.

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