MassIVE MSV000092468

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Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

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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 (GEMMs), 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 (MSI) 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 murine intestine was found 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. [doi:10.25345/C57H1DX66] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: adenosylhomocysteinase ; colorectal cancer ; metabolomics ; metabolism ; cancer ; methionine cycle

Contact

Principal Investigators:
(in alphabetical order) 		David sumpton, Cancer Research Beatson Institute, United Kingdom
Johan Vande Voorde, Cancer Research Beatson Institute, United Kingdom
Owen Sansom, Cancer Research Beatson Institute, United Kingdom
Submitting User: dsumpton

Publications

Vande Voorde J, Steven RT, Najumudeen AK, Ford CA, Dexter A, Gonzalez-Fernandez A, Nikula CJ, Xiang Y, Ford L, Maneta Stavrakaki S, Gilroy K, Zeiger LB, Pennel K, Hatthakarnkul P, Elia EA, Nasif A, Murta T, Manoli E, Mason S, Gillespie M, Lannagan TRM, Vlahov N, Ridgway RA, Nixon C, Raven A, Mills M, Athineos D, Kanellos G, Nourse C, Gay DM, Hughes M, Burton A, Yan B, Sellers K, Wu V, De Ridder K, Shokry E, Huerta Uribe A, Clark W, Clark G, Kirschner K, Thienpont B, Li VSW, Maddocks ODK, Barry ST, Goodwin RJA, Kinross J, Edwards J, Yuneva MO, Sumpton D, Takats Z, Campbell AD, Bunch J, Sansom OJ.
Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.
Nat Metab. 2023 Aug;5(8):1303-1318. Epub 2023 Aug 14.

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