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

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.

Mutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma

“…We also found significant enrichment of the hypoxia gene expression signature in LMSU gastric cancer cells retaining endogenous p53-R175H (normalized enrichment score [NES] = 1.84, FDR P = 0.007; Supplemental Figure 5C). Other results included upregulation of EMT genes, consistent with evidence supporting a role for mutant p53 in the mesenchymal phenotype and metastasis (21,24,27,34); and upregulation of mTOR pathway signatures, a result not validated by our analysis of phosphorylated AKT in xenografted p53-R175H LMSU tumors.…”

“…There is, however, evidence that mutant p53 can stabilize MDM2 expression in cancer (20), opening the possibility for other explanations for mutant p53 overexpression in cancer. It is conceivable that elevated protein expression of mutant p53 could also reflect potential pro-oncogenic activity, as previously reported in several tumors (21)(22)(23)(24)(25)(26)(27)(28). The observation that the majority of patients with TP53 mutant Barrett's metaplasia, a precursor to esophageal adenocarcinoma, and GEA selectively lose the remaining WT TP53 copy through LOH also raises the potential of a gain-of-function activity in addition to an established dominant-negative property (Supplemental Figure 1C).…”

Meta-analysis of targeted metabolomics data from heterogeneous biological samples provides insights into metabolite dynamics

“…Preparation of the sample types below has been described before Schofield et al, 2018;Sousa et al, 2016;Svoboda et al, 2018;Yuan et al, 2012). A brief description follows.…”

“…Our LC-MS/MS metabolomics analysis was performed as described previously Schofield et al, 2018;Sousa et al, 2016). In brief, an Agilent 1290 UHPLC and 6490 Triple Quadrupole (QqQ) Mass Spectrometer (LC-MS) were used for label-free targeted metabolomics analysis.…”

“…It utilizes both RPLC and HILIC methods with dynamic MRM (dMRM) as a means to maximize the coverage and sensitivity of target metabolites. Together with our customized computational and statistical analysis pipeline, this platform has been recently applied in several biological contexts Schofield et al, 2018;Sousa et al, 2016;Svoboda et al, 2018). Herein, we report heterogeneous data sets from a wide range of experiments and sample types that were generated on our LC-MS/MS targeted metabolomics platform over a period of one year.…”