@article{7403a76f31aa4d998746276c77c4950f,
title = "Docking Protein p130Cas Regulates Acinar to Ductal Metaplasia During Pancreatic Adenocarcinoma Development and Pancreatitis",
abstract = "Background & Aims: Acinar to ductal metaplasia is the prerequisite for the initiation of Kras-driven pancreatic ductal adenocarcinoma (PDAC), and candidate genes regulating this process are emerging from genome-wide association studies. The adaptor protein p130Cas emerged as a potential PDAC susceptibility gene and a Kras-synthetic lethal interactor in pancreatic cell lines; however, its role in PDAC development has remained largely unknown. Methods: Human PDAC samples and murine KrasG12D-dependent pancreatic cancer models of increasing aggressiveness were used. p130Cas was conditionally ablated in pancreatic cancer models to investigate its role during Kras-induced tumorigenesis. Results: We found that high expression of p130Cas is frequently detected in PDAC and correlates with higher histologic grade and poor prognosis. In a model of Kras-driven PDAC, loss of p130Cas inhibits tumor development and potently extends median survival. Deletion of p130Cas suppresses acinar-derived tumorigenesis and progression by means of repressing PI3K–AKT signaling, even in the presence of a worsening condition like pancreatitis. Conclusions: Our observations finally demonstrated that p130Cas acts downstream of Kras to boost the PI3K activity required for acinar to ductal metaplasia and subsequent tumor initiation. This demonstrates an unexpected driving role of p130Cas downstream of Kras through PI3K/AKT, thus indicating a rational therapeutic strategy of targeting the PI3K pathway in tumors with high expression of p130Cas.",
keywords = "ADM, Carcinogenesis, Kras, Metaplasia, PDAC",
author = "Andrea Costamagna and Dora Natalini and {Camacho Leal}, {Maria del Pilar} and Matilde Simoni and Luca Gozzelino and Paola Cappello and Francesco Novelli and Chiara Ambrogio and Paola Defilippi and Emilia Turco and Elisa Giovannetti and Emilio Hirsch and Sara Cabodi and Miriam Martini",
note = "Funding Information: Funding Sara Cabodi's laboratory is supported by Associazione Italiana per la Ricerca sul Cancro AIRC (IG11346). Miriam Martini is supported by a Worldwide Cancer Research grant (WWCR 20-0033). Emilio Hirsch is supported by AIRC (IG21875), Ministero Universit{\`a} Ricerca (PRIN 2017), and Leducq Transatlantic Network of Excellence (19CVD02). Elisa Giovannetti is supported by AIRC (IG24444) and Dutch Cancer Society (KWF-11957). Chiara Ambrogio{\textquoteright}s laboratory is supported by the Giovanni Armenise–Harvard Foundation and the Lung Cancer Research Foundation. Paola Defilippi is supported by AIRC (IG-20107), Compagnia San Paolo Torino (Progetto DEFLECT), Fondazione CRT (2020.1798). Funding Information: The authors would like to thank Dr Paolo Ettore Porporato and Dr Alessandro Carrer for critically reading the manuscript and useful discussion. Andrea Costamagna, PhD (Conceptualization: Equal; Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Writing ? original draft: Lead). Dora Natalini, MS (Data curation: Equal; Investigation: Equal; Writing ? review & editing: Equal). Maria del Pilar Camacho Leal, PhD (Conceptualization: Equal; Investigation: Equal). Matilde Simoni, MS (Investigation: Equal). Luca Gozzelino, MS (Investigation: Equal). Paola Cappello, PhD (Data curation: Equal; Methodology: Equal). Francesco Novelli, PhD (Data curation: Equal; Methodology: Equal). Chiara Ambrogio, PhD (Methodology: Equal; Resources: Equal; Visualization: Equal). Paola Defilippi, PhD (Formal analysis: Equal; Visualization: Equal). Emilia Turco, MS (Methodology: Equal; Resources: Equal). Elisa Giovannetti, MD, PhD (Conceptualization: Equal; Investigation: Equal; Methodology: Equal; Resources: Equal; Validation: Equal; Writing ? original draft: Equal). Emilio Hirsch, PhD (Funding acquisition: Equal; Visualization: Equal; Writing ? review & editing: Equal). Sara Cabodi, PhD (Conceptualization: Equal; Funding acquisition: Lead; Supervision: Equal). Miriam Martini, PhD (Conceptualization: Equal; Funding acquisition: Lead; Supervision: Equal). Funding Sara Cabodi's laboratory is supported by Associazione Italiana per la Ricerca sul Cancro AIRC (IG11346). Miriam Martini is supported by a Worldwide Cancer Research grant (WWCR 20-0033). Emilio Hirsch is supported by AIRC (IG21875), Ministero Universit? Ricerca (PRIN 2017), and Leducq Transatlantic Network of Excellence (19CVD02). Elisa Giovannetti is supported by AIRC (IG24444) and Dutch Cancer Society (KWF-11957). Chiara Ambrogio's laboratory is supported by the Giovanni Armenise?Harvard Foundation and the Lung Cancer Research Foundation. Paola Defilippi is supported by AIRC (IG-20107), Compagnia San Paolo Torino (Progetto DEFLECT), Fondazione CRT (2020.1798). Publisher Copyright: {\textcopyright} 2022 The Authors",
year = "2022",
month = apr,
day = "1",
doi = "https://doi.org/10.1053/j.gastro.2021.12.242",
language = "English",
volume = "162",
pages = "1242--1255.e11",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "4",
}