Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.
Creators: name: Voorde, Johan Vande
name: Steven, Rory T
name: Najumudeen, Arafath K
name: Ford, Catriona A
name: Dexter, Alex
name: Gonzalez-Fernandez, Ariadna
name: Nikula, Chelsea J
name: Xiang, Yuchen
name: Ford, Lauren
name: Stavrakaki, Stefania Maneta
name: Gilroy, Kathryn
name: Zeiger, Lucas B
name: Pennel, Kathryn
name: Hatthakarnkul, Phimmada
name: Elia, Efstathios A
name: Nasif, Ammar
name: Murta, Teresa
name: Manoli, Eftychios
name: Mason, Sam
name: Gillespie, Michael
name: Lannagan, Tamsin RM
name: Vlahov, Nikola
name: Ridgway, Rachel A
name: Nixon, Colin
name: Raven, Alexander
name: Mills, Megan
name: Athineos, Dimitris
name: Kanellos, Georgios
name: Nourse, Craig
name: Gay, David M
name: Hughes, Mark
name: Burton, Amy
name: Yan, Bin
name: Sellers, Katherine
name: Wu, Vincen
name: De Ridder, Kobe
name: Shokry, Engy
name: Uribe, Alejandro Huerta
name: Clark, William
name: Clark, Graeme
name: Kirschner, Kristina
name: Thienpont, Bernard
name: Li, Vivian SW
name: Maddocks, Oliver DK
name: Barry, Simon T
name: Goodwin, Richard JA
name: Kinross, James
name: Edwards, Joanne
name: Yuneva, Mariia O
name: Sumpton, David
name: Takats, Zoltan
name: Campbell, Andrew D
name: Bunch, Josephine
name: Sansom, Owen J
Publisher: name: The Francis Crick Institute
Year: 2023
Subjects: classificationCode: Tumour Biology
subject: Tumour Biology
classificationCode: Stem Cells
subject: Stem Cells
classificationCode: Signalling & Oncogenes
subject: Signalling &amp; Oncogenes
classificationCode: Metabolism
subject: Metabolism
classificationCode: Developmental Biology
subject: Developmental Biology
classificationCode: Computational & Systems Biology
subject: Computational &amp; Systems Biology
classificationCode: Genome Integrity & Repair
subject: Genome Integrity &amp; Repair
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms

description: 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.