p53 mutations cooperate with oncogenic Kras to promote adenocarcinoma from pancreatic ductal cells

• Published in: Oncogene 2016-08, Vol.35 (32), p.4282-4288
• Main Authors: Bailey, J M, Hendley, A M, Lafaro, K J, Pruski, M A, Jones, N C, Alsina, J, Younes, M, Maitra, A, McAllister, F, Iacobuzio-Donahue, C A, Leach, S D
• Format: Article
• Language: English
• Subjects: 13/51; 14; 14/1; 14/63; 631/67/68; 64/110; Acinar cells; Adenocarcinoma; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Animals; Apoptosis; Cancer; Carcinogenesis; Cell Biology; Cell Line, Tumor; Cellular biology; Cellular Senescence; Epithelium; Human Genetics; Humans; Internal Medicine; Invasiveness; K-Ras protein; Medicine; Medicine & Public Health; Mice; Mutants; Mutation; Oncology; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Phosphoproteins - metabolism; Proto-Oncogene Proteins p21(ras) - metabolism; short-communication; Signal Transduction; STAT3 Transcription Factor - metabolism; Tumor Suppressor Protein p53 - genetics; Tumors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.441

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.