Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target
Year: 2023
Type: article
Abstract: The genomic landscape of colorectal cancer (CRC) is shaped by inactivating mutations in tumour suppressors such as APC , and oncogenic mutations such as mutant KRAS . Here we used genetically engineered mouse models, and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that untargeted metabolic profiling can be applied to stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-deficient CRC. Loss of Apc in the mouse intestine was found to be sufficient to drive expression of one of its enzymes, adenosylhomocysteinase (AHCY), which was also found to be transcriptionally upregulated in human CRC. Targeting of AHCY function impaired growth of APC-deficient organoids in vitro, and prevented the characteristic hyperproliferative/crypt progenitor phenotype driven by acute deletion of Apc in vivo, even in the context of mutant Kras . Finally, pharmacological inhibition of AHCY reduced intestinal tumour burden in Apc Min/+ mice indicating its potential as a metabolic drug target in CRC.
Source: Nature Metabolism
Authors: Johan Vande Voorde, Rory T. Steven, Arafath K. Najumudeen, Catriona A. Ford, Alex Dexter, Ariadna Gonzalez-Fernandez, Chelsea J. Nikula, Yuchen Xiang, Lauren Ford, Stefania Maneta Stavrakaki, Kathryn Gilroy, Lucas B. Zeiger, Kathryn Pennel, Phimmada Hatthakarnkul, Efstathios A. Elia, Ammar Nasif, Teresa Murta, Eftychios Manoli, Sam Mason, Michael Gillespie, Tamsin R. M. Lannagan, Nikola Vlahov, Rachel A. Ridgway, Colin Nixon, Alexander Raven, Megan Mills, Dimitris Athineos, Georgios Kanellos, Craig Nourse, David M. Gay, Mark Hughes, Amy Burton, Bin Yan, Katherine Sellers, Vincen Wu, Kobe De Ridder, Engy Shokry, Alejandro Huerta Uribe, William Clark, Graeme Clark, Kristina Kirschner, Bernard Thienpont, Vivian S. W. Li, Oliver D. K. Maddocks, Simon T. Barry, Richard J. A. Goodwin, James Kinross, Joanne Edwards, Mariia O. Yuneva, David Sumpton, Zoltan Takats, Andrew D. Campbell, Josephine Bunch, Owen J. Sansom
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $11,690
Funders: Cooley's Anemia Foundation, Wellcome Trust, Francis Crick Institute, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, University of Glasgow, Fonds Wetenschappelijk Onderzoek, Vlaamse regering, Medical Research Council, Engineering and Physical Sciences Research Council, Invention for Innovation Programme, Invention for Innovation, Medical Research Foundation
Awards: G1089133943, G1215785162, G1222568953, G136381397, G180086439, G2031823047, G2038315422, Regulation of protein synthesis by elongation control in health and disease, G2210802987, G2225267780, G2250849917, WIME: WNT-mediated immune evasion in intestinal homeostasis, regeneration and cancer, G244503085, G248282384, G2500740911, G2769569657, G2853087268, G294389965, G3574825762, G3768580956, G382092367, G4002584958, G4382047161, G4583068110, G5131144263, G5280137580, G5300649118, G5322340622, G5484707053, G5556509577, iEndoscope: Colonoscopy Using Rapid Evaporative Ionization Mass Spectrometry (REIMS) for precision phenotyping of colonic adenomas and early colorectal cancer., G5718954505, G5980734565, G6301641109, G6475537503, G6738704210, G6863181770, G7029987583, G7099308606, Regulation of protein synthesis by elongation control in health and disease, G8101666146, G8603525355
OpenAlex ID: W4385827399