학술논문
Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target
Document Type
Original Paper
Author
Vande Voorde, Johan; Steven, Rory T.; Najumudeen, Arafath K.; Ford, Catriona A.; Dexter, Alex; Gonzalez-Fernandez, Ariadna; Nikula, Chelsea J.; Xiang, Yuchen; Ford, Lauren; Maneta Stavrakaki, Stefania; Gilroy, Kathryn; Zeiger, Lucas B.; Pennel, Kathryn; Hatthakarnkul, Phimmada; Elia, Efstathios A.; Nasif, Ammar; Murta, Teresa; Manoli, Eftychios; Mason, Sam; Gillespie, Michael; Lannagan, Tamsin R. M.; Vlahov, Nikola; Ridgway, Rachel A.; Nixon, Colin; Raven, Alexander; Mills, Megan; Athineos, Dimitris; Kanellos, Georgios; Nourse, Craig; Gay, David M.; Hughes, Mark; Burton, Amy; Yan, Bin; Sellers, Katherine; Wu, Vincen; De Ridder, Kobe; Shokry, Engy; Huerta Uribe, Alejandro; Clark, William; Clark, Graeme; Kirschner, Kristina; Thienpont, Bernard; Li, Vivian S. W.; Maddocks, Oliver D. K.; Barry, Simon T.; Goodwin, Richard J. A.; Kinross, James; Edwards, Joanne; Yuneva, Mariia O.; Sumpton, David; Takats, Zoltan; Campbell, Andrew D.; Bunch, Josephine; Sansom, Owen J.
Source
Nature Metabolism. 5(8):1303-1318
Subject
Language
English
ISSN
2522-5812
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 ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.
In this study, Vande Voorde et al. investigate the potential of untargeted metabolomics as a stratification tool for colorectal cancer (CRC). They present a comprehensive pipeline to uncover metabolic vulnerabilities in CRC based on its genetic origin. With this approach, they show perturbations in methionine metabolism linked to APC deficiency, and identify adenosylhomocysteinase as an actionable therapeutic target.
In this study, Vande Voorde et al. investigate the potential of untargeted metabolomics as a stratification tool for colorectal cancer (CRC). They present a comprehensive pipeline to uncover metabolic vulnerabilities in CRC based on its genetic origin. With this approach, they show perturbations in methionine metabolism linked to APC deficiency, and identify adenosylhomocysteinase as an actionable therapeutic target.