Mutant p53R270H drives altered metabolism and increased invasion in pancreatic ductal adenocarcinoma

Heather K. Schofield, Jörg Zeller, Carlos Espinoza, Christopher J. Halbrook, Annachiara Del Vecchio, Brian Magnuson, Tania Fabo, Ayse Ece Cali Daylan, Ilya Kovalenko, Ho Joon Lee, Wei Yan, Ying Feng, Saadia A. Karim, Daniel M. Kremer, Chandan Kumar-Sinha, Costas A. Lyssiotis, Mats Ljungman, Jennifer P. Morton, Stefanie Galbán, Eric R. FearonMarina Pasca di Magliano

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Pancreatic cancer is characterized by nearly universal activating mutations in KRAS. Among other somatic mutations, TP53 is mutated in more than 75% of human pancreatic tumors. Genetically engineered mice have proven instrumental in studies of the contribution of individual genes to carcinogenesis. Oncogenic Kras mutations occur early during pancreatic carcinogenesis and are considered an initiating event. In contrast, mutations in p53 occur later during tumor progression. In our model, we recapitulated the order of mutations of the human disease, with p53 mutation following expression of oncogenic Kras. Further, using an inducible and reversible expression allele for mutant p53, we inactivated its expression at different stages of carcinogenesis. Notably, the function of mutant p53 changes at different stages of carcinogenesis. Our work establishes a requirement for mutant p53 for the formation and maintenance of pancreatic cancer precursor lesions. In tumors, mutant p53 becomes dispensable for growth. However, it maintains the altered metabolism that characterizes pancreatic cancer and mediates its malignant potential. Further, mutant p53 promotes epithelial-mesenchymal transition (EMT) and cancer cell invasion. This work generates new mouse models that mimic human pancreatic cancer and expands our understanding of the role of p53 mutation, common in the majority of human malignancies.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number2
DOIs
StatePublished - Jan 25 2018

All Science Journal Classification (ASJC) codes

  • General Medicine

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