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, 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 Min/+ mice indicating its potential as a metabolic drug target in CRC.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature Metabolism |
| Vol/bind | 5 |
| Udgave nummer | 8 |
| Sider (fra-til) | 1303-1318 |
| Antal sider | 16 |
| ISSN | 2522-5812 |
| DOI | |
| Status | Udgivet - 2023 |
Bibliografisk note
Funding Information:We thank all members of the Grand Challenge Rosetta consortium, E. Gottlieb, J. R. P. Knight, J. Balzarini, V. H. Cowling, M. Bushell, T. G. Bird and C. Winchester for discussion of the data and manuscript. We thank G. Thomson and L. Mcgarry for help with IF image acquisition. We are grateful to the Cancer Research UK (CRUK) Beatson Institute Central Services, Molecular Technology Service, Histology Service, the Transgenic Technology Laboratory, the Beatson Advanced Imaging Resource and the Biological Services Unit for technical support. We thank the Francis Crick Institute’s Biological Research Facilities and Experimental Histopathology for managing mouse colonies and tissue processing. O.J.S. was supported by grants from CRUK (A21139, A25045, A17196, A31287). J.V.V., A.K.N., D.M.G., L.B.Z., C.A.F., A.D.C., R.T.S., A.D., A.G.-F., C.J.N., E.A.E., A.N., T.M., A.B., B.Y., Y.X., S.M.S., V.W., K.S., M.O.Y., Z.T. and J.B. were supported by the CRUK Rosetta Grand Challenge (A25045, A24034, A25043, A25038). D.S., M.M., G.K., C. Nixon., R.A.R., E.S., A.H.U., M.H., W.C., G.C. and A.D.C. were supported by the CRUK Beatson Institute core grant (A17196 and A31287 to O.J.S.). D.A. was supported by the CRUK Beatson Institute core grant A29799. N.V. was supported by the Wellcome Trust (201487 to O.J.S.). K.G. and A.R. were supported by the CRUK Grand Challenge Specificancer Grand Challenge Consortium (A29055 to O.J.S.). T.R.M.L. and A.D.C. were funded by CRUK Accelerator Award (A26825 to O.J.S.). O.D.K.M. was funded by a CRUK Career Development Fellowship (C53309/A19702). M.G. was funded by the University of Glasgow. S.M. was supported by a CRUK PhD fellowship (WSSS_P69974). K.P. was funded by Chief Scientific Office TCS/22/02. P.H. was funded by CRUK (RRNPSF-JUL21/1D100010). J.E., K.K. and C. Nourse were funded by CRUK Scotland Centre funding (CTRQQR-2021/100006). B.T. and K.D.R. were supported by The Research Foundation–Flanders (1524119N). This work was supported by the Francis Crick Institute, which receives its core funding from CRUK (FC001223, CC2141), the UK Medical Research Council (FC001223, CC2141) and the Wellcome Trust (FC001223, FC0010060, CC2141). This study was funded by the NIHR Invention for Innovation programme (II-LB-1116-20005). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
We thank all members of the Grand Challenge Rosetta consortium, E. Gottlieb, J. R. P. Knight, J. Balzarini, V. H. Cowling, M. Bushell, T. G. Bird and C. Winchester for discussion of the data and manuscript. We thank G. Thomson and L. Mcgarry for help with IF image acquisition. We are grateful to the Cancer Research UK (CRUK) Beatson Institute Central Services, Molecular Technology Service, Histology Service, the Transgenic Technology Laboratory, the Beatson Advanced Imaging Resource and the Biological Services Unit for technical support. We thank the Francis Crick Institute’s Biological Research Facilities and Experimental Histopathology for managing mouse colonies and tissue processing. O.J.S. was supported by grants from CRUK (A21139, A25045, A17196, A31287). J.V.V., A.K.N., D.M.G., L.B.Z., C.A.F., A.D.C., R.T.S., A.D., A.G.-F., C.J.N., E.A.E., A.N., T.M., A.B., B.Y., Y.X., S.M.S., V.W., K.S., M.O.Y., Z.T. and J.B. were supported by the CRUK Rosetta Grand Challenge (A25045, A24034, A25043, A25038). D.S., M.M., G.K., C. Nixon., R.A.R., E.S., A.H.U., M.H., W.C., G.C. and A.D.C. were supported by the CRUK Beatson Institute core grant (A17196 and A31287 to O.J.S.). D.A. was supported by the CRUK Beatson Institute core grant A29799. N.V. was supported by the Wellcome Trust (201487 to O.J.S.). K.G. and A.R. were supported by the CRUK Grand Challenge Specificancer Grand Challenge Consortium (A29055 to O.J.S.). T.R.M.L. and A.D.C. were funded by CRUK Accelerator Award (A26825 to O.J.S.). O.D.K.M. was funded by a CRUK Career Development Fellowship (C53309/A19702). M.G. was funded by the University of Glasgow. S.M. was supported by a CRUK PhD fellowship (WSSS_P69974). K.P. was funded by Chief Scientific Office TCS/22/02. P.H. was funded by CRUK (RRNPSF-JUL21/1D100010). J.E., K.K. and C. Nourse were funded by CRUK Scotland Centre funding (CTRQQR-2021/100006). B.T. and K.D.R. were supported by The Research Foundation–Flanders (1524119N). This work was supported by the Francis Crick Institute, which receives its core funding from CRUK (FC001223, CC2141), the UK Medical Research Council (FC001223, CC2141) and the Wellcome Trust (FC001223, FC0010060, CC2141). This study was funded by the NIHR Invention for Innovation programme (II-LB-1116-20005). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Publisher Copyright:
© 2023, The Author(s).