Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

Abstract

Background:
To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.

Methods:
We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2–4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.

Results:
We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor—CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.

Conclusions:
Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.

People
Holt, Amy K.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Najumudeen, Arafath K.
Author

Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT Consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D. (2024) Author Correction: Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56 (6): 1321. ISSN 1061-4036

Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D. (2024) Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56 (3). pp. 458-472. ISSN 1061-4036

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Collard, Tracey J.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Li, Hao
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Millett, Laura M.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Hoskin, Ashley J.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Legge, Danny N.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Mortensson, Eleanor M.H.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Flanagan, Dustin J.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Jones, Nicholas
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Kollareddy, Madhu
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Timms, Penny
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Hitchings, Matthew D.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Cronin, James
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Sansom, Owen
Author

Lu, Yuting and Travnickova, Jana and Badonyi, Mihaly and Rambow, Florian and Coates, Andrea and Khan, Zaid and Marques, Jair and Murphy, Laura C. and Garcia-Martinez, Pablo and Marais, Richard and Louphrasitthiphol, Pakavarin and Chan, Alex H.Y. and Schofield, Christopher J. and von Kriegsheim, Alex and Marsh, Joseph A. and Pavet, Valeria and Sansom, Owen J. and Illingworth, Robert S. and Patton, E. Elizabeth (2024) ALDH1A3-acetaldehyde metabolism potentiates transcriptional heterogeneity in melanoma. Cell Reports, 43 (7): 114406. ISSN 2639-1856

Pereira, Brooke A. and Ritchie, Shona and Chambers, Cecilia R. and Gordon, Katie A. and Magenau, Astrid and Murphy, Kendelle J. and Nobis, Max and Tyma, Victoria M. and Liew, Ying Fei and Lucas, Morghan C. and Naeini, Marjan M. and Barkauskas, Deborah S. and Chacon-Fajardo, Diego and Howell, Anna E. and Parker, Amelia L. and Warren, Sean C. and Reed, Daniel A. and Lee, Victoria and Metcalf, Xanthe L. and Lee, Young Kyung and O'Regan, Luke P. and Zhu, Jessie and Trpceski, Michael and Fontaine, Angela R.M. and Stoehr, Janett and Rouet, Romain and Lin, Xufeng and Chitty, Jessica L. and Porazinski, Sean and Wu, Sunny Z. and Filipe, Elysse C. and Cadell, Antonia L. and Holliday, Holly and Yang, Jessica and Papanicolaou, Michael and Lyons, Ruth J. and Zaratzian, Anaiis and Tayao, Michael and Da Silva, Andrew and Vennin, Claire and Yin, Julia and Dew, Alysha B. and McMillan, Paul J. and Goldstein, Leonard D. and Deveson, Ira W. and Croucher, David R. and Samuel, Michael S. and Sim, Hao-Wen and Batten, Marcel and Chantrill, Lorraine and Grimmond, Sean M. and Gill, Anthony J. and Samra, Jaswinder and Evans, Thomas R. Jeffry and Sasaki, Takako and Phan, Tri G. and Swarbrick, Alexander and Sansom, Owen J. and Morton, Jennifer P. and Australian Pancreatic Cancer Matrix Atlas (APMA) and Australian Pancreatic Cancer Genome Initiative (APGI) and Pajic, Marina and Parker, Benjamin L. and Herrmann, David and Cox, Thomas R. and Timpson, Paul (2024) Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response. Science Advances, 10 (27): eadl1197. ISSN 2375-2548

Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT Consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D. (2024) Author Correction: Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56 (6): 1321. ISSN 1061-4036

See full publications list
Williams, Ann C.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
Vincent, Emma E.
Author

Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E. (2023) Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition. Cancer and Metabolism, 11 (1): 18. ISSN 2049-3002

See full publications list
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Title:
Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition
Creators:
Holt, Amy K. and Najumudeen, Arafath K. and Collard, Tracey J. and Li, Hao and Millett, Laura M. and Hoskin, Ashley J. and Legge, Danny N. and Mortensson, Eleanor M.H. and Flanagan, Dustin J. and Jones, Nicholas and Kollareddy, Madhu and Timms, Penny and Hitchings, Matthew D. and Cronin, James and Sansom, Owen J. and Williams, Ann C. and Vincent, Emma E.
Identification Number:
10.1186/s40170-023-00318-y
Date:
19 October 2023
Divisions:
College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher:
BioMed Central
Library
URI:
https://pub.demo35.eprints-hosting.org/id/eprint/481
Item Type:
Article
Depositing User:
Unnamed user with email ejo1f20@soton.ac.uk
SWORD Depositor:
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Date Deposited:
11 Jun 2025 16:38
Revision:
14
Last Modified:
12 Jun 2025 09:22
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