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Identifying targetable metabolic dependencies across colorectal cancer progression

Danny N. Legge, Tracey J. Collard, Ewelina Stanko, Ashley J. Hoskin, Amy K. Holt, Caroline J. Bull, Madhu Kollareddy, Jake Bellamy, Sarah Groves, Eric H. Ma, Emma Hazelwood, David Qualtrough, Borko Amulic, Karim Malik, Ann C. Williams, Nick Jones Orcid Logo, Emma E. Vincent Orcid Logo

Molecular Metabolism, Volume: 90, Start page: 102037

Swansea University Author: Nick Jones Orcid Logo

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DOI (Published version): 10.1016/j.molmet.2024.102037

Abstract

Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As...

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Published in: Molecular Metabolism
ISSN: 2212-8778
Published: Elsevier BV 2024
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URI: https://cronfa.swan.ac.uk/Record/cronfa67838
first_indexed 2024-09-26T07:42:23Z
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However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system &#x2013; comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.</abstract><type>Journal Article</type><journal>Molecular Metabolism</journal><volume>90</volume><journalNumber/><paginationStart>102037</paginationStart><paginationEnd/><publisher>Elsevier BV</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint>2212-8778</issnPrint><issnElectronic/><keywords>Colorectal cancer; Oncometabolism; Asparagine; Asparagine synthetase; Adenoma; Adenocarcinoma</keywords><publishedDay>1</publishedDay><publishedMonth>12</publishedMonth><publishedYear>2024</publishedYear><publishedDate>2024-12-01</publishedDate><doi>10.1016/j.molmet.2024.102037</doi><url/><notes/><college>COLLEGE NANME</college><department>Medical School</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>MEDS</DepartmentCode><institution>Swansea University</institution><apcterm>Another institution paid the OA fee</apcterm><funders>We thank D. Avizonis and L. Choini&#xE8;re from McGill University Metabolomics Core Facility, Kate Heesom and Phil Lewis from University of Bristol Proteomics Facility and the Wolfson Bioimaging Facility at the University of Bristol. EEV, DNL and CJB are supported by Diabetes UK (17/0005587) and the Worldwide Cancer Research Fund (WCRF UK), as part of the Worldwide Cancer Research Fund International grant program (IIG_2019_2009). SG is funded by Above and Beyond Charity and BA is supported by MRC grant MR/R02149X/1. EEV and ACW are supported by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). EEV and CJB work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 &amp; MC_UU_00011/4) and the University of Bristol. 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spelling 2024-10-16T14:37:32.5427257 v2 67838 2024-09-26 Identifying targetable metabolic dependencies across colorectal cancer progression 0fce0f7ddbdbfeb968f4e2f1e3f86744 0000-0003-4846-5117 Nick Jones Nick Jones true false 2024-09-26 MEDS Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease. Journal Article Molecular Metabolism 90 102037 Elsevier BV 2212-8778 Colorectal cancer; Oncometabolism; Asparagine; Asparagine synthetase; Adenoma; Adenocarcinoma 1 12 2024 2024-12-01 10.1016/j.molmet.2024.102037 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University Another institution paid the OA fee We thank D. Avizonis and L. Choinière from McGill University Metabolomics Core Facility, Kate Heesom and Phil Lewis from University of Bristol Proteomics Facility and the Wolfson Bioimaging Facility at the University of Bristol. EEV, DNL and CJB are supported by Diabetes UK (17/0005587) and the Worldwide Cancer Research Fund (WCRF UK), as part of the Worldwide Cancer Research Fund International grant program (IIG_2019_2009). SG is funded by Above and Beyond Charity and BA is supported by MRC grant MR/R02149X/1. EEV and ACW are supported by the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). EEV and CJB work in a unit funded by the UK Medical Research Council (MC_UU_00011/1 & MC_UU_00011/4) and the University of Bristol. AKH and AJH are supported by the James Tudor Foundation; John and Bridget Maynard; and John James Bristol Foundation. 2024-10-16T14:37:32.5427257 2024-09-26T08:40:37.4249746 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Biomedical Science Danny N. Legge 1 Tracey J. Collard 2 Ewelina Stanko 3 Ashley J. Hoskin 4 Amy K. Holt 5 Caroline J. Bull 6 Madhu Kollareddy 7 Jake Bellamy 8 Sarah Groves 9 Eric H. Ma 10 Emma Hazelwood 11 David Qualtrough 12 Borko Amulic 13 Karim Malik 14 Ann C. Williams 15 Nick Jones 0000-0003-4846-5117 16 Emma E. Vincent 0000-0002-8917-7384 17 67838__32612__ae5940a0adf54ca0a2d35592f6728455.pdf 67838.VoR.pdf 2024-10-16T13:47:20.4541243 Output 3960826 application/pdf Version of Record true Copyright: 2024 The Authors. This is an open access article under the CC BY license. true eng http://creativecommons.org/licenses/by/4.0/
title Identifying targetable metabolic dependencies across colorectal cancer progression
spellingShingle Identifying targetable metabolic dependencies across colorectal cancer progression
Nick Jones
title_short Identifying targetable metabolic dependencies across colorectal cancer progression
title_full Identifying targetable metabolic dependencies across colorectal cancer progression
title_fullStr Identifying targetable metabolic dependencies across colorectal cancer progression
title_full_unstemmed Identifying targetable metabolic dependencies across colorectal cancer progression
title_sort Identifying targetable metabolic dependencies across colorectal cancer progression
author_id_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744
author_id_fullname_str_mv 0fce0f7ddbdbfeb968f4e2f1e3f86744_***_Nick Jones
author Nick Jones
author2 Danny N. Legge
Tracey J. Collard
Ewelina Stanko
Ashley J. Hoskin
Amy K. Holt
Caroline J. Bull
Madhu Kollareddy
Jake Bellamy
Sarah Groves
Eric H. Ma
Emma Hazelwood
David Qualtrough
Borko Amulic
Karim Malik
Ann C. Williams
Nick Jones
Emma E. Vincent
format Journal article
container_title Molecular Metabolism
container_volume 90
container_start_page 102037
publishDate 2024
institution Swansea University
issn 2212-8778
doi_str_mv 10.1016/j.molmet.2024.102037
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Biomedical Science{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Biomedical Science
document_store_str 0
active_str 0
description Colorectal cancer (CRC) is a multi-stage process initiated through the formation of a benign adenoma, progressing to an invasive carcinoma and finally metastatic spread. Tumour cells must adapt their metabolism to support the energetic and biosynthetic demands associated with disease progression. As such, targeting cancer cell metabolism is a promising therapeutic avenue in CRC. However, to identify tractable nodes of metabolic vulnerability specific to CRC stage, we must understand how metabolism changes during CRC development. Here, we use a unique model system – comprising human early adenoma to late adenocarcinoma. We show that adenoma cells transition to elevated glycolysis at the early stages of tumour progression but maintain oxidative metabolism. Progressed adenocarcinoma cells rely more on glutamine-derived carbon to fuel the TCA cycle, whereas glycolysis and TCA cycle activity remain tightly coupled in early adenoma cells. Adenocarcinoma cells are more flexible with respect to fuel source, enabling them to proliferate in nutrient-poor environments. Despite this plasticity, we identify asparagine (ASN) synthesis as a node of metabolic vulnerability in late-stage adenocarcinoma cells. We show that loss of asparagine synthetase (ASNS) blocks their proliferation, whereas early adenoma cells are largely resistant to ASN deprivation. Mechanistically, we show that late-stage adenocarcinoma cells are dependent on ASNS to support mTORC1 signalling and maximal glycolytic and oxidative capacity. Resistance to ASNS loss in early adenoma cells is likely due to a feedback loop, absent in late-stage cells, allowing them to sense and regulate ASN levels and supplement ASN by autophagy. Together, our study defines metabolic changes during CRC development and highlights ASN synthesis as a targetable metabolic vulnerability in later stage disease.
published_date 2024-12-01T20:48:04Z
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