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

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.

Metadata

Item Type:	Article
Authors/Creators:	Malla, S.B. https://orcid.org/0000-0001-5862-3815 Byrne, R.M. https://orcid.org/0000-0001-6505-6345 Lafarge, M.W. Corry, S.M. Fisher, N.C. https://orcid.org/0000-0003-1769-7468 Tsantoulis, P.K. https://orcid.org/0000-0003-3613-6682 Mills, M.L. Ridgway, R.A. https://orcid.org/0000-0003-0198-8244 Lannagan, T.R.M. Najumudeen, A.K. Gilroy, K.L. https://orcid.org/0000-0003-4607-194X Amirkhah, R. https://orcid.org/0000-0003-3494-271X Maguire, S.L. https://orcid.org/0000-0001-6654-3620 Mulholland, E.J. https://orcid.org/0000-0002-1200-9825 Belnoue-Davis, H.L. https://orcid.org/0000-0003-2914-4932 Grassi, E. https://orcid.org/0000-0003-1066-927X Viviani, M. https://orcid.org/0000-0003-4698-8870 Rogan, E. Redmond, K.L. Sakhnevych, S. McCooey, A.J. Bull, C. Hoey, E. Sinevici, N. Hall, H. https://orcid.org/0000-0003-2779-2565 Ahmaderaghi, B. https://orcid.org/0000-0003-4166-6290 Domingo, E. https://orcid.org/0000-0003-4390-8767 Blake, A. Richman, S.D. https://orcid.org/0000-0003-3993-5041 Isella, C. Miller, C. Bertotti, A. Trusolino, L. https://orcid.org/0000-0002-6379-3365 Loughrey, M.B. Kerr, E.M. https://orcid.org/0000-0002-1952-4213 Tejpar, S. https://orcid.org/0000-0003-3281-8643 Maughan, T.S. Lawler, M. Campbell, A.D. https://orcid.org/0000-0003-3930-1276 Leedham, S.J. https://orcid.org/0000-0003-1476-6982 Koelzer, V.H. https://orcid.org/0000-0001-9206-4885 Sansom, O.J. https://orcid.org/0000-0001-9540-3010 Dunne, P.D. https://orcid.org/0000-0001-9160-283X
Copyright, Publisher and Additional Information:	© The Author(s) 2024. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Published: March 2024 Published (online): 13 February 2024 Accepted: 3 January 2023
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Medical Research (LIMR) > Division of Pathology and Data Analytics
Funding Information:	Funder Grant number Cancer Research UK Supplier No: 138573 R2683CNR
Depositing User:	Symplectic Publications
Date Deposited:	20 Feb 2024 16:35
Last Modified:	21 May 2024 07:53
Published Version:	https://www.nature.com/articles/s41588-024-01654-5
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41588-024-01654-5
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:209420

CORE (COnnecting REpositories)

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

Abstract

Metadata

Download

Published Version

Export

Statistics