posted on 2023-09-01, 10:38authored byJohan 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 RM 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 SW Li, Oliver DK Maddocks, Simon T Barry, Richard JA Goodwin, James Kinross, Joanne Edwards, Mariia O Yuneva, David Sumpton, Zoltan Takats, Andrew D Campbell, Josephine Bunch, Owen J Sansom
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.
Funding
Crick (Grant ID: CC2082, Grant title: Yuneva CC2082)
Crick (Grant ID: CC2141, Grant title: Li CC2141)