Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

Malla, S. B. et al. (2024) Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56(3), pp. 458-472. (doi: 10.1038/s41588-024-01654-5) (PMID:38351382)

Abstract

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.

• Item Type: Articles
• Additional Information: This work was supported by a Cancer Research UK (CRUK) early detection grant (P.D.D.; A29834), a CRUK International accelerator program (ACRCelerate) (P.D.D., O.J.S., S.J.L., M.L. and T.S.M.; A26825), a UK Medical Research Council (MRC) and CRUK co-funded Stratified Medicine Consortium program grant (S:CORT) (P.D.D., M.L. and T.S.M.; MR/M016587/1), an MRC National Mouse Genetics Network program (P.D.D. and S.J.L.; MC_PC_21042), CRUK Beatson institute funding (O.J.S.; A21139, A17196 and A31287). CRUK program grant (S.J.L.; DRCNPG-Jun22\100002), Lee Placito Medical Research Fund (E.J.M.; University of Oxford), Health Data Research UK Grant (M.L.), AIRC– Associazione Italiana per la Ricerca sul Cancro, Investigator Grants 20697 (A.B.) and 22802 (L.T.), Promedica Foundation F-87701-41-01 (V.H.K.), a My First AIRC Grant (C.I.; ID 19047); AIRC 5×1000 grant 21091 (L.T., A.B.); European Research Council Consolidator Grant 724748 BEAT (A.B.); H2020 grant agreement no. 754923 COLOSSUS (L.T.); H2020 INFRAIA grant agreement no. 731105 EDIReX (A.B.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, 5×1000 Ministero della Salute 2016 (L.T.); BOF-Fundamental Clinical Research mandate from KU Leuven and by the Belgian Foundation Against Cancer (S.T.; FAF-C/2018/1301).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Miller, Professor Crispin and Sansom, Professor Owen
• Authors: Malla, S. B., Byrne, R. M., Lafarge, M. W., Corry, S. M., Fisher, N. C., Tsantoulis, P. K., Mills, M. L., Ridgway, R. A., Lannagan, T. R. M., Najumudeen, A. K., Gilroy, K. L., Amirkhah, R., Maguire, S. L., Mulholland, E. J., Belnoue-Davis, H. L., Grassi, E., Viviani, M., Rogan, E., Redmond, K. L., Sakhnevych, S., McCooey, A. J., Bull, C., Hoey, E., Sinevici, N., Hall, H., Ahmaderaghi, B., Domingo, E., Blake, A., Richman, S. D., Isella, C., Miller, C., Bertotti, A., Trusolino, L., Loughrey, M. B., Kerr, E. M., Tejpar, S., Maughan, T. S., Lawler, M., Campbell, A. D., Leedham, S. J., Koelzer, V. H., Sansom, O. J., and Dunne, P. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Genetics
• Publisher: Nature Research
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Published Online: 13 February 2024
• Copyright Holders: Copyright © 2024 The Author(s)
• First Published: First published in Nature Genetics 56(3):458-472
• Publisher Policy: Reproduced under a Creative Commons license