Dataset Information

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

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 (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.

INSTRUMENT(S): Xevo G2 XS Tof, TSQ Altis, Xevo G2-XS QTof, SYNAPT G2-Si, Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606) Mus Musculus (ncbitaxon:10090)

SUBMITTER: David sumpton Johan Vande Voorde Owen Sansom

PROVIDER: MSV000092468 | GNPS | Tue Jul 18 07:53:00 BST 2023

REPOSITORIES: GNPS

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

Vande Voorde Johan J Steven Rory T RT Najumudeen Arafath K AK Ford Catriona A CA Dexter Alex A Gonzalez-Fernandez Ariadna A Nikula Chelsea J CJ Xiang Yuchen Y Ford Lauren L Maneta Stavrakaki Stefania S Gilroy Kathryn K Zeiger Lucas B LB Pennel Kathryn K Hatthakarnkul Phimmada P Elia Efstathios A EA Nasif Ammar A Murta Teresa T Manoli Eftychios E Mason Sam S Gillespie Michael M Lannagan Tamsin R M TRM Vlahov Nikola N Ridgway Rachel A RA Nixon Colin C Raven Alexander A Mills Megan M Athineos Dimitris D Kanellos Georgios G Nourse Craig C Gay David M DM Hughes Mark M Burton Amy A Yan Bin B Sellers Katherine K Wu Vincen V De Ridder Kobe K Shokry Engy E Huerta Uribe Alejandro A Clark William W Clark Graeme G Kirschner Kristina K Thienpont Bernard B Li Vivian S W VSW Maddocks Oliver D K ODK Barry Simon T ST Goodwin Richard J A RJA Kinross James J Edwards Joanne J Yuneva Mariia O MO Sumpton David D Takats Zoltan Z Campbell Andrew D AD Bunch Josephine J Sansom Owen J OJ

Nature metabolism 20230814 8

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, ...[more]

PMID: 37580540

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Project description:Inflammatory bowel diseases (IBD) in humans are characterized by chronic inflammation and gastrointestinal tissue damage, caused by a combination of genetic and environmental factors. It has been largely documented that IBD frequently lead to colorectal cancers (CRC). The identification of causative factors of IBD is thus essential to understand CRC progression and develop therapeutical approaches. Models have been described in which molecular alterations are combined with inflammatory treatments in order to recapitulate IBD-associated CRC. Here, we describe a mouse line, Î±6fl/fl Villin-Cre, in which inactivation of the gene encoding the integrin alpha-6 subunit (ITGA6) specifically in the intestinal mucosa results into chronic inflammation and intestinal carcinogenesis. In these mice, the loss of integrin alpha-6 beta-4, a receptor mediating the attachment of epithelial cells to laminins, leads to epithelial detachment, hyperplasia, chronic inflammation, rectal prolapses, and ultimately adenocarcinomas. Alterations of differentiation affecting mucus secreting (goblet) cells as well as changes in expression of essential intestinal transcription factors were detected. Thus alpha-6 beta-4 integrin is a key factor for the maintenance of intestinal integrity and its loss may represent a risk factor for tumor progression associated with IBD. Transcriptome analysis of RNA from normal versus inflamed and carcinomatous rectal mucosa of Î±6 integrin deficient intestinal epithelium mice was performed. RNAs were prepared from 5 adenocarcinomas, which were macrodissected from the rectal prolapses and 4 flanking inflamed rectal mucosa of 53-80 week-old Î±6fl/fl Villin-Cre mice. RNAs from normal rectal mucosa were obtained by rectum scraping from 4 matched control animals. The transcriptome analysis was performed using the Affymetrix Mouse Gene 1.0 ST arrays. Images were processed using affymetrix GeneChipÂ® Command ConsoleÂ® Software (AGCC) (version 2.0) and numerical value were generated using Affymetrix Expression Consoleâ¢ Software (version 1.1).