title: p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells.
abstract: Pancreatic cancer is one of the most lethal malignancies, with virtually all patients eventually succumbing to their disease. Mutations in p53 have been documented in >50% of pancreatic cancers. Owing to the high incidence of p53 mutations in PanIN 3 lesions and pancreatic tumors, we interrogated the comparative ability of adult pancreatic acinar and ductal cells to respond to oncogenic Kras and mutant Tp53(R172H) using Hnf1b:CreER(T2) and Mist1:CreER(T2) mice. These studies involved co-activation of a membrane-tethered GFP lineage label, allowing for direct visualization and isolation of cells undergoing Kras and mutant p53 activation. Kras activation in Mist1(+) adult acinar cells resulted in brisk PanIN formation, whereas no evidence of pancreatic neoplasia was observed for up to 6 months following Kras activation in Hnf1beta(+) adult ductal cells. In contrast to the lack of response to oncogenic Kras alone, simultaneous activation of Kras and mutant p53 in adult ductal epithelium generated invasive PDAC in 75% of mice as early as 2.5 months after tamoxifen administration. These data demonstrate that pancreatic ductal cells, whereas exhibiting relative resistance to oncogenic Kras alone, can serve as an effective cell of origin for pancreatic ductal adenocarcinoma in the setting of gain-of-function mutations in p53.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Bailey
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Hendley
authors.affiliation: The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Lafaro
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Pruski
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: N C
authors.initials: NC
authors.lastname: Jones
authors.affiliation: Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Alsina
authors.affiliation: Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Younes
authors.affiliation: Departments of Pathology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Maitra
authors.affiliation: Departments of Clinical Cancer Prevention and GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: McAllister
authors.affiliation: The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: The David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Leach
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D006801:Humans; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D010750:Phosphoproteins; D050796:STAT3 Transcription Factor; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras)