PCK1 and DHODH drive colorectal cancer liver metastatic colonization and nucleotide biosynthesis under hypoxia

Abstract

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

RBMS1 Suppresses Colon Cancer Metastasis through Targeted Stabilization of Its mRNA Regulon

“…We used RNA-seq data from three parental CRC PDX models (CLR4, CLR27, and CLR32) and their highly liver metastatic derivatives (CLR-LvMs). The highly metastatic CLR-LvM models were derived from the parental PDXs by repeated splenic delivery and growth of cells in the liver of immunocompromised mice (NOD scid gamma), recapitulating the major site of CRC metastasis in humans (9). We observed that the increase in the metastatic capacity of the CLR-LvM PDX models compared to their parental PDXs was accompanied by a significant reduction in the expression of the RBMS1 regulon in the highly metastatic CLR-LvM models (Fig.…”