Regulation of Epithelial Plasticity Determines Metastatic Organotropism in Pancreatic Cancer

• Type of Material: Article
• Authors: Maximillian Reichert, University of Pennsylvania; Basil Bakir, University of Pennsylvania; Leticia Moreira, University of Pennsylvania; Jason R. Pitarresi, University of Pennsylvania; Karin Feldmann, Technical University of Munich; Lauren Simon, University of Pennsylvania; Kensuke Suzuki, University of Pennsylvania; Ravikanth Maddipati, University of Pennsylvania; Andrew D. Rhim, MD Anderson Cancer Center; Anna M. Schlitter, Technical University of Munich; Mark Kriegsmann, Heidelberg University; Wilko Weichert, Technical University of Munich; Matthias Wirth, Heinrich Heine University; Kathleen Schuck, Technical University of Munich; Gunter Schneider, Technical University of Munich; Dieter Saur, Technical University of Munich; Albert B. Reynolds, Vanderbilt University; Andres J. Klein-Szanto, Fox Chase Cancer Center; Burcin Pehlivanoglu, Emory University; Bahar Memis, Emory University; Volkan Adsay, Emory University; Anil K. Rustgi, University of Pennsylvania
• Language: English
• Date: 2018-06-18
• Publisher: Elsevier (Cell Press)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Elsevier Inc.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.devcel.2018.05.025
• Title of Journal or Parent Work: Developmental Cell
• ISSN: 1534-5807
• Volume: 45
• Issue: 6
• Start Page: 696
• End Page: +
• Grant/Funding Information: We thank the following funding sources: F30 CA180601 (BB and AKR), R01 DK060694 (MR and AKR), American Cancer Society (AKR), National Pancreas Foundation (MR), German Cancer Aid Foundation (Max Eder Program, Deutsche Krebshilfe 111273, MR), KKF Program (School of Medicine, Klinikum rechts der Isar, Technical University Munich, MR), AGA-Actavis Research Award in Pancreatic Disorders (MR), Asociación Española Contra el Cáncer (Programa Avanzado en Oncología 2016, LM), Societat Catalatana de Digestologia (Beca d’estada a l’estranger 2015, LM), and F32CA221094 (JP).; Part of this work was funded by the German Consortium for Translational Cancer Research (DKTK) and the BMBF-funded PANC-STRAT consortium (grant no. 01ZX1305 and 01ZX1605 to WW).
• Keywords: Developmental Biology; Cell Biology; CADHERIN; P120-CATENIN; P120 CATENIN; Life Sciences & Biomedicine; REGENERATION; Science & Technology; TUMOR-SUPPRESSOR; MESENCHYMAL TRANSITION; RECOMBINASE; EMT; INFLAMMATION; INVASION
• Research Categories: Biology, Cell

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.