PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis

• DOI: 10.7554/elife.52135
• Publication Date: 2019-12-16T13:00:17Z
• Authors: Norihiro Yamaguchi; Ethan M Weinberg; Alexander Nguyen; Maria V Liberti; Hani Goodarzi; Yelena Y Janjigian; Philip B Paty; Leonard B Saltz; T Peter Kingham; Jia Min Loo; Elisa de Stanchina; Sohail F Tavazoie
• Keywords: Pyrimidine metabolism

Colorectal cancer (CRC) is a major cause of human death. Mortality primarily due to metastatic organ colonization, with the liver being main affected. We modeled CRC (mCRC) colonization using patient-derived primary and tumor xenografts (PDX). Such PDX modeling predicted patient survival outcomes. In vivo selection multiple PDXs for enhanced capacity upregulated gluconeogenic enzyme PCK1, which growth by driving pyrimidine nucleotide biosynthesis under hypoxia. Consistently, highly tumors intermediary metabolites. Therapeutic inhibition biosynthetic DHODH leflunomide substantially impaired hypoxic growth. Our findings provide potential mechanistic basis epidemiologic association anti-gluconeogenic drugs improved metastasis outcomes, reveal exploitation gluconeogenesis hypoxia, implicate PCK1 as metabolic therapeutic targets in progression.