PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis
- The Rockefeller University, United States
- 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
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mRNA sequencing of highly and lowly metastatic human colorectal cancer PDXsNCBI Gene Expression Omnibus, GSE138248.
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Gene expression profiling study by RNA-seq in colorectal cancerNCBI Gene Expression Omnibus, GSE50760.
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Whole genome analysis for liver metastasis gene signitures in colorectal cancerNCBI Gene Expression Omnibus, GSE6988.
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Expression Profile of Primary Colorectal Cancers and associated Liver MetastasesNCBI Gene Expression Omnibus, GSE14297.
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Expression data from colorectal cancer patientsNCBI Gene Expression Omnibus, GSE41258.
Article and author information
Author details
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.
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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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
Further reading
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- Cancer Biology
Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
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