Martinez-Val, AnaVan der Hoeven, LeanderBekker-Jensen, Dorte BJørgensen, Margarita MelnikovaNors, JesperFranciosa, GiuliaAndersen, Claus LBramsen, Jesper BOlsen, Jesper V2025-07-232025-07-232025-07Mol Syst Biol. 2025 Jul;21(7):776-806.https://hdl.handle.net/20.500.12105/26841Colorectal cancer molecular signatures derived from omics data can be employed to stratify CRC patients and aid decisions about therapies or evaluate prognostic outcome. However, molecular biomarkers for identification of patients at increased risk of disease relapse are currently lacking. Here, we present a comprehensive multi-omics analysis of a Danish colorectal cancer tumor cohort composed of 412 biopsies from tumors of 371 patients diagnosed at TNM stage II or III. From mass spectrometry-based patient proteome profiles, we classified the tumors into four molecular subtypes, including a mesenchymal-like subtype. As the mesenchymal-rich tumors are known to represent the most invasive and metastatic phenotype, we focused on the protein signature defining this subtype to evaluate their potential as relapse risk markers. Among signature-specific proteins, we followed-up Caveolae-Associated Protein-1 (CAVIN1) and demonstrated its role in tumor progression in a 3D in vitro model of colorectal cancer. Compared to previous omics analyses of CRC, our multi-omics classification provided deeper insights into EMT in cancer cells with stronger correlations with risk of relapse.Work at The Novo Nordisk Foundation Center for Protein Research (CPR) is funded in part by a donation from the Novo Nordisk Foundation (NNF14CC0001 and NNF24SA0098829). Part of this work has been funded as part of the MSmed project that has received funding from the European Union’s Horizon 2020 Research and Innovation program under grant agreement no. 686547 and as part of EPIC-XS project under the grant agreement no. 823839. This project was supported by a generous grant from the Danish Agency of Higher Education and Science to establish the PLATO research infrastructure: Danish National Mass Spectrometry Platform for Proteomics and Biomolecular Imaging (grant no. 5229-00012B).engVoRhttp://creativecommons.org/licenses/by/4.0/CAVIN1Colorectal CancerProteomicsTumor RelapseAttribution 4.0 International40269326Molecular Systems Biologyopen access