PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis. Academic Article uri icon

Overview

abstract

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

publication date

  • December 16, 2019

Research

keywords

  • Colorectal Neoplasms
  • Hypoxia
  • Intracellular Signaling Peptides and Proteins
  • Liver Neoplasms
  • Nucleotides
  • Oxidoreductases Acting on CH-CH Group Donors
  • Phosphoenolpyruvate Carboxykinase (GTP)

Identity

PubMed Central ID

  • PMC7299340

Scopus Document Identifier

  • 85078221191

Digital Object Identifier (DOI)

  • 10.18632/oncotarget.18787

PubMed ID

  • 31841108

Additional Document Info

volume

  • 8