Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
24
02
2022
accepted:
06
07
2023
medline:
25
8
2023
pubmed:
15
8
2023
entrez:
14
8
2023
Statut:
ppublish
Résumé
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 Apc
Identifiants
pubmed: 37580540
doi: 10.1038/s42255-023-00857-0
pii: 10.1038/s42255-023-00857-0
pmc: PMC10447251
doi:
Substances chimiques
Adenosylhomocysteinase
EC 3.3.1.1
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
AHCY protein, human
EC 3.3.1.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1303-1318Subventions
Organisme : Cancer Research UK
ID : A25045
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : FC001223
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A21139
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A19702
Pays : United Kingdom
Organisme : Arthritis Research UK
ID : CC2141
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29799
Pays : United Kingdom
Organisme : Cancer Research UK
ID : FC001223
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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