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

  1. Norihiro Yamaguchi
  2. Ethan M Weinberg
  3. Alexander Nguyen
  4. Maria V Liberti
  5. Hani Goodarzi
  6. Yelena Y Janjigian
  7. Philip B Paty
  8. Leonard B Saltz
  9. T Peter Kingham
  10. Jia Min Loo
  11. Elisa de Stanchina
  12. Sohail F Tavazoie  Is a corresponding author
  1. The Rockefeller University, United States
  2. Memorial Sloan-Kettering Cancer Center, United States

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.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE138248

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Norihiro Yamaguchi

    Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ethan M Weinberg

    Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Alexander Nguyen

    Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6578-3454
  4. Maria V Liberti

    Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hani Goodarzi

    Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yelena Y Janjigian

    Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Philip B Paty

    Colorectal Service, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Leonard B Saltz

    Gastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. T Peter Kingham

    Hepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jia Min Loo

    Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Elisa de Stanchina

    Antitumor Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Sohail F Tavazoie

    Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United States
    For correspondence
    stavazoie@mail.rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4966-9018

Funding

National Center for Advancing Translational Sciences (UL1 TR001866)

  • Norihiro Yamaguchi
  • Ethan M Weinberg

Meyer Foundation

  • Norihiro Yamaguchi

The Helmsley Charitable trust

  • Norihiro Yamaguchi

National Institute of General Medical Sciences (T32GM07739)

  • Alexander Nguyen

NIH Office of the Director (T32CA009673-36A1)

  • Hani Goodarzi

NIH Office of the Director (1K99CA194077-01)

  • Hani Goodarzi

National Cancer Institute (K00CA222986)

  • Maria V Liberti

Starr Foundation

  • Sohail F Tavazoie

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved protocol, The Rockefeller University Institutional Animal Care and Use Committee (protocol 15783-H).

Human subjects: Approval for the study was obtained through the MSKCC Institutional Review Board/Privacy Board (protocol 10-018A), the MSKCC Institutional Animal Care and Use Committee (protocol 04-03-009), The Rockefeller University Institutional Review Board (protocol STA-0681), Written consent was obtained from all human participants who provided samples for patient-derived xenografts.

Reviewing Editor

  1. William C. Hahn, Dana-Farber Cancer Institue, United States

Publication history

  1. Received: September 23, 2019
  2. Accepted: December 15, 2019
  3. Accepted Manuscript published: December 16, 2019 (version 1)
  4. Accepted Manuscript updated: December 23, 2019 (version 2)
  5. Version of Record published: January 24, 2020 (version 3)

Copyright

© 2019, Yamaguchi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Norihiro Yamaguchi
  2. Ethan M Weinberg
  3. Alexander Nguyen
  4. Maria V Liberti
  5. Hani Goodarzi
  6. Yelena Y Janjigian
  7. Philip B Paty
  8. Leonard B Saltz
  9. T Peter Kingham
  10. Jia Min Loo
  11. Elisa de Stanchina
  12. Sohail F Tavazoie
(2019)
PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis
eLife 8:e52135.
https://doi.org/10.7554/eLife.52135

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    This study’s literature retrieval was supported financially by the 345 Talent Project of Shengjing Hospital of China Medical University (M0949 to Tao Zhang).