Vande Voorde, J. et al. (2023) Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target. Nature Metabolism, 5(8), pp. 1303-1318. (doi: 10.1038/s42255-023-00857-0) (PMID:37580540) (PMCID:PMC10447251)
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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 ApcMin/+ mice indicating its potential as a metabolic drug target in CRC.
| Item Type: | Articles |
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| Additional Information: | 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). |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Clark, Mr William and Pennel, Miss Kathryn and Ford, Miss Catriona and Sumpton, Mr David and Huerta Uribe, Mr Alejandro and Hughes, Mr Mark and Gilroy, Dr Kathryn and Zeiger, Lucas and Gillespie, Michael and Nixon, Mr Colin and Mills, Ms Megan and Kirschner, Dr Kristina and Gay, David and Athineos, Mr Dimitris and Edwards, Professor Joanne and Goodwin, Dr Richard and Ridgway, Dr Rachel and Nourse, Dr Craig and Hatthakarnkul, Phimmada and Maddocks, Professor Oliver and Sansom, Professor Owen and Campbell, Dr Andrew |
| Authors: | Vande Voorde, J., Steven, R. T., Najumudeen, A. K., Ford, C. A., Dexter, A., Gonzalez-Fernandez, A., Nikula, C. J., Xiang, Y., Ford, L., Maneta Stavrakaki, S., Gilroy, K., Zeiger, L. B., Pennel, K., Hatthakarnkul, P., Elia, E. A., Nasif, A., Murta, T., Manoli, E., Mason, S., Gillespie, M., Lannagan, T. R.M., Vlahov, N., Ridgway, R., Nixon, C., Raven, A., Mills, M., Athineos, D., Kanellos, G., Nourse, C., Gay, D. M., 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, V. S.W., Maddocks, O. D.K., Barry, S. T., Goodwin, R. J.A., Kinross, J., Edwards, J., Yuneva, M. O., Sumpton, D., Takats, Z., Campbell, A. D., Bunch, J., and Sansom, O. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Nature Metabolism |
| Publisher: | Nature Research |
| ISSN: | 2522-5812 |
| ISSN (Online): | 2522-5812 |
| Published Online: | 14 August 2023 |
| Copyright Holders: | Copyright © 2023 The Authors |
| First Published: | First published in Nature Metabolism 5(8): 1303-1318 |
| Publisher Policy: | Reproduced under a Creative Commons license |
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