@article{72d61a5c9ba9459ab35f55fed4cc809d,
title = "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. 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.",
keywords = "E-cadherin, epithelial plasticity, metastasis, organotropism, p120catenin, p120catenin isoform, pancreatic cancer",
author = "Maximilian Reichert and Basil Bakir and Leticia Moreira and Pitarresi, {Jason R.} and Karin Feldmann and Lauren Simon and Kensuke Suzuki and Ravikanth Maddipati and Rhim, {Andrew D.} and Schlitter, {Anna M.} and Mark Kriegsmann and Wilko Weichert and Matthias Wirth and Kathleen Schuck and G{\"u}nter Schneider and Dieter Saur and Reynolds, {Albert B.} and Klein-Szanto, {Andres J.} and Burcin Pehlivanoglu and Bahar Memis and Adsay, {N. Volkan} and Rustgi, {Anil K.}",
note = "Funding Information: We express our gratitude to the NIH /NIDDK P30-DK050306 Center for Molecular Studies in Digestive and Liver Diseases (and Molecular Pathology and Imaging, H-MARC, Cell Culture, and Transgenic and Chimeric Mouse Cores) as well as the Flow Cytometry/Sorting Core. We thank the following funding sources: F30 CA180601 (B.B. and A.K.R.), R01 DK060694 (M.R. and A.K.R.), American Cancer Society (A.K.R.), National Pancreas Foundation (M.R.), German Cancer Aid Foundation (Max Eder Program, Deutsche Krebshilfe 111273 , M.R.), KKF Program (School of Medicine, Klinikum rechts der Isar, Technical University of Munich , MR), AGA-Actavis Research Award in Pancreatic Disorders (M.R.), Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (Programa Avanzado en Oncolog{\'i}a 2016; L.M.), Societat Catalatana de Digestologia (Beca d'estada an l'estranger 2015, L.M.), and F32CA221094 (J.R.P.). 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 W.W.). We wish to thank Dr. Nicole Aiello (University of Pennsylvania, Laboratory of Dr. Ben Stanger) for generously providing us tissue from KPCY mice; Dr. Andrea Califano (Columbia University) for generously providing us human PNET samples; and Dr. Carmen Guerra (Centro Nacional de Investigaciones Oncol{\'o}gicas, Madrid, Spain) for generously providing us Elastase-driven inducible KRAS G12V PDAC tissue. Funding Information: We express our gratitude to the NIH/NIDDK P30-DK050306 Center for Molecular Studies in Digestive and Liver Diseases (and Molecular Pathology and Imaging, H-MARC, Cell Culture, and Transgenic and Chimeric Mouse Cores) as well as the Flow Cytometry/Sorting Core. We thank the following funding sources: F30 CA180601 (B.B. and A.K.R.), R01 DK060694 (M.R. and A.K.R.), American Cancer Society (A.K.R.), National Pancreas Foundation (M.R.), German Cancer Aid Foundation (Max Eder Program, Deutsche Krebshilfe 111273, M.R.), KKF Program (School of Medicine, Klinikum rechts der Isar, Technical University of Munich, MR), AGA-Actavis Research Award in Pancreatic Disorders (M.R.), Asociaci{\'o}n Espa{\~n}ola Contra el C{\'a}ncer (Programa Avanzado en Oncolog{\'i}a 2016; L.M.), Societat Catalatana de Digestologia (Beca d'estada an l'estranger 2015, L.M.), and F32CA221094 (J.R.P.). 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 W.W.). We wish to thank Dr. Nicole Aiello (University of Pennsylvania, Laboratory of Dr. Ben Stanger) for generously providing us tissue from KPCY mice; Dr. Andrea Califano (Columbia University) for generously providing us human PNET samples; and Dr. Carmen Guerra (Centro Nacional de Investigaciones Oncol{\'o}gicas, Madrid, Spain) for generously providing us Elastase-driven inducible KRASG12V PDAC tissue. Funding Information: We express our gratitude to the NIH/NIDDK P30-DK050306 Center for Molecular Studies in Digestive and Liver Diseases (and Molecular Pathology and Imaging, H-MARC, Cell Culture, and Transgenic and Chimeric Mouse Cores) as well as the Flow Cytometry/Sorting Core. We thank the following funding sources: F30 CA180601 (B.B. and A.K.R.), R01 DK060694 (M.R. and A.K.R.), American Cancer Society (A.K.R.), National Pancreas Foundation (M.R.), German Cancer Aid Foundation (Max Eder Program, Deutsche Krebshilfe 111273, M.R.), KKF Program (School of Medicine, Klinikum rechts der Isar, Technical University of Munich, MR), AGA-Actavis Research Award in Pancreatic Disorders (M.R.), Asociaci?n Espa?ola Contra el C?ncer (Programa Avanzado en Oncolog?a 2016; L.M.), Societat Catalatana de Digestologia (Beca d'estada an l'estranger 2015, L.M.), and F32CA221094 (J.R.P.). 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 W.W.). We wish to thank Dr. Nicole Aiello (University of Pennsylvania, Laboratory of Dr. Ben Stanger) for generously providing us tissue from KPCY mice; Dr. Andrea Califano (Columbia University) for generously providing us human PNET samples; and Dr. Carmen Guerra (Centro Nacional de Investigaciones Oncol?gicas, Madrid, Spain) for generously providing us Elastase-driven inducible KRASG12V PDAC tissue. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jun,
day = "18",
doi = "10.1016/j.devcel.2018.05.025",
language = "English (US)",
volume = "45",
pages = "696--711.e8",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "6",
}