Metabolic Coordination of Tumor Suppression

Abstract

Increasing evidence demonstrates that intracellular metabolic pathways can be critical drivers of tumor progression. Metabolites provide the biomass required for cancer cell proliferation and contribute to antioxidant defenses that promote survival and metastatic dissemination. Moreover, oncogenic mutations in several metabolic enzymes lead to accumulation of pathological levels of metabolites that interfere with histone and DNA demethylation and impose a block to differentiation. Thus, while the ability of metabolites to contribute directly to malignant progression is well established, whether metabolites can contribute to the cell fate changes that occur during tumor suppression remains an open question. To study the role of metabolism during tumor suppression, we took advantage of a mouse model of pancreatic ductal adenocarcinoma driven by mutant Kras and inducible suppression of p53 to enable temporal control of tumor suppression. Using cell lines derived from these tumors, we found that p53 restoration is accompanied by metabolic alterations that can be uncoupled from changes in cell cycle progression. Recapitulating these metabolic alterations with pharmacologic or genetic interventions in malignant cells is sufficient to phenocopy the effects of p53 restoration on differentiation and tumor progression. These results suggest that p53‐driven metabolic rewiring directly contributes to the cell fate changes that occur during tumor suppression.Support or Funding InformationThis work was supported by the Searle Scholars Program, the Damon Runyon Cancer Research Foundation (DFS‐23‐17) and The Starr Foundation (I11‐0039).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.