PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis Journal Article
| Authors: | Yamaguchi, N.; Weinberg, E. M.; Nguyen, A.; Liberti, M. V.; Goodarzi, H.; Janjigian, Y. Y.; Paty, P. B.; Saltz, L. B.; Kingham, T. P.; Loo, J. M.; de Stanchina, E.; Tavazoie, S. F. |
| Article Title: | PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis |
| Abstract: | Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with the 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 colonization capacity upregulated the gluconeogenic enzyme PCK1, which enhanced liver metastatic hypoxic 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 colorectal cancer metastatic progression. © 2019, eLife Sciences Publications Ltd. All rights reserved. |
| Keywords: | cancer survival; controlled study; protein expression; treatment outcome; unclassified drug; human cell; cancer growth; nonhuman; flow cytometry; colorectal cancer; animal cell; mouse; animal tissue; gene expression profiling; animal experiment; animal model; tumor xenograft; transcriptomics; hypoxia; genetic transfection; real time polymerase chain reaction; rna extraction; tumor engraftment; metastatic colorectal cancer; liquid chromatography-mass spectrometry; gluconeogenesis; isotope tracing; nucleotide metabolism; liver histology; phosphoenolpyruvate carboxykinase (gtp); leflunomide; colorectal liver metastasis; hypoxic cell; human; article; rna sequencing; cell growth assay; 3 mercaptopicolinic acid; pyrimidine synthesis; metabolic fingerprinting; dihydroorotate dehydrogenase; phosphoenolpyruvate carboxykinase 1; colon adenocarcinoma cell line |
| Journal Title: | eLife |
| Volume: | 8 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2019-12-16 |
| Start Page: | e52135 |
| Language: | English |
| DOI: | 10.7554/eLife.52135 |
| PUBMED: | 31841108 |
| PROVIDER: | scopus |
| PMCID: | PMC7299340 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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