Journal article 133 views
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 
,
Emma E. Vincent
,
Emma E. Vincent
Molecular Metabolism, Volume: 90, Start page: 102037
Swansea University Author:
Nick Jones
Full text not available from this repository: check for access using links below.
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...
| Published in: | Molecular Metabolism |
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| ISSN: | 2212-8778 |
| Published: |
Elsevier BV
2024
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa67838 |
| 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 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. |
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| Keywords: |
Colorectal cancer; Oncometabolism; Asparagine; Asparagine synthetase; Adenoma; Adenocarcinoma |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
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. |
| Start Page: |
102037 |