PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis
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 modeli...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2019-12-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/52135 |
| _version_ | 1818026952924069888 |
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| author | Norihiro Yamaguchi Ethan M Weinberg Alexander Nguyen Maria V Liberti Hani Goodarzi Yelena Y Janjigian Philip B Paty Leonard B Saltz T Peter Kingham Jia Min Loo Elisa de Stanchina Sohail F Tavazoie |
| author_facet | Norihiro Yamaguchi Ethan M Weinberg Alexander Nguyen Maria V Liberti Hani Goodarzi Yelena Y Janjigian Philip B Paty Leonard B Saltz T Peter Kingham Jia Min Loo Elisa de Stanchina Sohail F Tavazoie |
| author_sort | Norihiro Yamaguchi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T04:40:11Z |
| format | Article |
| id | doaj.art-df6349d3163c42688775653c831ce857 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T04:40:11Z |
| publishDate | 2019-12-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-df6349d3163c42688775653c831ce8572022-12-22T02:01:55ZengeLife Sciences Publications LtdeLife2050-084X2019-12-01810.7554/eLife.52135PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesisNorihiro Yamaguchi0https://orcid.org/0000-0001-8023-9748Ethan M Weinberg1Alexander Nguyen2https://orcid.org/0000-0001-6578-3454Maria V Liberti3Hani Goodarzi4Yelena Y Janjigian5Philip B Paty6Leonard B Saltz7T Peter Kingham8Jia Min Loo9Elisa de Stanchina10Sohail F Tavazoie11https://orcid.org/0000-0002-4966-9018Laboratory of Systems Cancer Biology, The Rockefeller University, New York, United StatesLaboratory of Systems Cancer Biology, The Rockefeller University, New York, United StatesLaboratory of Systems Cancer Biology, The Rockefeller University, New York, United StatesLaboratory of Systems Cancer Biology, The Rockefeller University, New York, United StatesLaboratory of Systems Cancer Biology, The Rockefeller University, New York, United StatesGastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, United StatesColorectal Service, Memorial Sloan-Kettering Cancer Center, New York, United StatesGastrointestinal Oncology Service, Memorial Sloan-Kettering Cancer Center, New York, United StatesHepatopancreatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, United StatesLaboratory of Systems Cancer Biology, The Rockefeller University, New York, United StatesAntitumor Assessment Core Facility, Memorial Sloan-Kettering Cancer Center, New York, United StatesLaboratory of Systems Cancer Biology, The Rockefeller University, New York, United States; Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, United StatesColorectal 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.https://elifesciences.org/articles/52135mousecancer metabolismcancer metastasis |
| spellingShingle | Norihiro Yamaguchi Ethan M Weinberg Alexander Nguyen Maria V Liberti Hani Goodarzi Yelena Y Janjigian Philip B Paty Leonard B Saltz T Peter Kingham Jia Min Loo Elisa de Stanchina Sohail F Tavazoie PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis eLife mouse cancer metabolism cancer metastasis |
| title | PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis |
| title_full | PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis |
| title_fullStr | PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis |
| title_full_unstemmed | PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis |
| title_short | PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis |
| title_sort | pck1 and dhodh drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis |
| topic | mouse cancer metabolism cancer metastasis |
| url | https://elifesciences.org/articles/52135 |
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