title: Pancreatic cell plasticity and cancer initiation induced by oncogenic Kras is completely dependent on wild-type PI 3-kinase p110α.
abstract: Increased PI 3-kinase (PI3K) signaling in pancreatic ductal adenocarcinoma (PDAC) correlates with poor prognosis, but the role of class I PI3K isoforms during its induction remains unclear. Using genetically engineered mice and pharmacological isoform-selective inhibitors, we found that the p110α PI3K isoform is a major signaling enzyme for PDAC development induced by a combination of genetic and nongenetic factors. Inactivation of this single isoform blocked the irreversible transition of exocrine acinar cells into pancreatic preneoplastic ductal lesions by oncogenic Kras and/or pancreatic injury. Hitting the other ubiquitous isoform, p110β, did not prevent preneoplastic lesion initiation. p110α signaling through small GTPase Rho and actin cytoskeleton controls the reprogramming of acinar cells and regulates cell morphology in vivo and in vitro. Finally, p110α was necessary for pancreatic ductal cancers to arise from Kras-induced preneoplastic lesions by increasing epithelial cell proliferation in the context of mutated p53. Here we identify an in vivo context in which p110α cellular output differs depending on the epithelial transformation stage and demonstrate that the PI3K p110α is required for PDAC induced by oncogenic Kras, the key driver mutation of PDAC. These data are critical for a better understanding of the development of this lethal disease that is currently without efficient treatment.
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France;
authors.forename: Romain
authors.initials: R
authors.lastname: Baer
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France;
authors.forename: Célia
authors.initials: C
authors.lastname: Cintas
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France;
authors.forename: Marlène
authors.initials: M
authors.lastname: Dufresne
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France;
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Cassant-Sourdy
authors.affiliation: Department of Internal Medicine 2, Technische Universität München, 81675 Munich, Germany;
authors.forename: Nina
authors.initials: N
authors.lastname: Schönhuber
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France;
authors.forename: Laetitia
authors.initials: L
authors.lastname: Planque
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France;
authors.forename: Hubert
authors.initials: H
authors.lastname: Lulka
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France;
authors.forename: Bettina
authors.initials: B
authors.lastname: Couderc
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France;
authors.forename: Corinne
authors.initials: C
authors.lastname: Bousquet
authors.affiliation: UMR1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Inserm, F-31000 Toulouse, France; Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France;
authors.forename: Barbara
authors.initials: B
authors.lastname: Garmy-Susini
authors.affiliation: Cell Signaling, UCL Cancer Institute, University College London, London WC1E 6DD, United Kingdom;
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France;
authors.forename: Stéphane
authors.initials: S
authors.lastname: Pyronnet
authors.affiliation: Department of Internal Medicine 2, Technische Universität München, 81675 Munich, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: UMR1037, Le Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm, F-31000 Toulouse, France; UMR1037, CRCT, Université Toulouse III-Paul Sabatier, F-31000 Toulouse, France; Equipe Labellisée Ligue Contre le Cancer, F-31000 Toulouse, France;
authors.forename: Julie
authors.initials: J
authors.lastname: Guillermet-Guibert
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000503:physiopathology*; D049109:Cell Proliferation; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D058543:Class Ia Phosphatidylinositol 3-Kinase; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: PI3K isoforms; genetic mouse models; oncogenes; pancreas; signaling; transdifferentiation