{
  "abstract": "Background Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, with clinical progress limited by intratumoural cellular diversity and the absence of robust, informative markers.Objective Leveraging the heterogeneity of cancer-associated fibroblasts (CAFs) within the tumour microenvironment, this study aims to identify and evaluate candidate biomarkers to support patient stratification and improve prediction of therapeutic responses.Design We applied a multiomic approach integrating single-cell RNA sequencing, computational cell deconvolution and protein-level assessment from patient tumours, complemented by in vitro and in vivo preclinical models, to characterise stromal populations linked to CRC progression and treatment resistance.Results Retrospective analysis of over 3000 patient samples across multiple cohorts identified a distinct subset of CAFs expressing collagen triple helix repeat containing 1 (CTHRC1). CTHRC1(+) CAFs were associated with increased transforming growth factor-beta (TGF-beta) signalling and poor clinical outcomes in early and advanced disease stages. CTHRC1(+) CAFs enabled stratification of both mismatch repair-deficient/microsatellite instability (dMMR/MSI) and mismatch repair-proficient/microsatellite stability (pMMR/MSS) tumours into immune-inflamed and poorly immunogenic subtypes. Retrospective analysis of several clinical trials revealed that CTHRC1(+) CAFs are linked to resistance to immune checkpoint inhibitors in MSI and MSS tumours, suggesting therapeutic potential for combining TGF-beta blockade with immunotherapy.Conclusion CTHRC1-expressing CAFs represent clinically relevant biomarkers that link molecular profiling with diagnostic pathology. Our findings support the potential incorporation of CTHRC1(+) CAF assessment into routine histopathological workflows, pending prospective validation, and suggest a framework for stroma-informed CRC stratification, particularly in patients with stroma-rich, treatment-resistant tumours and pMMR/MSS with limited therapeutic options.",
  "authors": [
    {
      "affiliations": [
        "Department of Pathology, Hospital del Mar, Barcelona, Spain",
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain",
        "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain"
      ],
      "name": "Mar Iglesias Coma"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Jordi Badia-Ramentol"
    },
    {
      "affiliations": [
        "Department of Pathology, Hospital Clínico Universitario, University of Valencia, Valencia, Spain",
        "INCLIVA Biomedical Research Institute, Valencia, Spain"
      ],
      "name": "Carolina Martinez-Ciarpaglini"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain",
        "Department of Medical Oncology, Hospital del Mar, Barcelona, Spain"
      ],
      "name": "Jenniffer Linares"
    },
    {
      "affiliations": [
        "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain",
        "INCLIVA Biomedical Research Institute, Valencia, Spain",
        "Department of Medical Oncology, Hospital Clinico Universitario, University of Valencia, Valencia, Spain"
      ],
      "name": "Noelia Tarazona"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Catalan Institute of Oncology (ICO) Badalona, Badalona, Spain",
        "Germans Trias I Pujol Research Institute (IGTP), Badalona, Spain"
      ],
      "name": "Nuria Mulet-Margalef"
    },
    {
      "affiliations": [
        "Department of Pathology, Hospital del Mar, Barcelona, Spain"
      ],
      "name": "Paula Tornero-Piñero"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Anna Sallent-Aragay"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Alba Recort-Bascuas"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Joan Gibert"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Marta Sant-Albors"
    },
    {
      "affiliations": [
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain",
        "Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands"
      ],
      "name": "Daniele V F Tauriello"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Melba Cruz-Moral"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Marina Carreras-Gallardo"
    },
    {
      "affiliations": [
        "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain",
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain"
      ],
      "name": "Elena Sancho"
    },
    {
      "affiliations": [
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain"
      ],
      "name": "Clara Morral Martinez"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Marta Garrido"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Catalan Institute of Oncology (ICO) Badalona, Badalona, Spain",
        "Germans Trias I Pujol Research Institute (IGTP), Badalona, Spain"
      ],
      "name": "Jose Luis Manzano Mozo"
    },
    {
      "affiliations": [
        "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain",
        "INCLIVA Biomedical Research Institute, Valencia, Spain",
        "Department of Medical Oncology, Hospital Clinico Universitario, University of Valencia, Valencia, Spain"
      ],
      "name": "Andrés Cervantes"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain",
        "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain",
        "Department of Medical Oncology, Hospital del Mar, Barcelona, Spain",
        "Pompeu Fabra University, Barcelona, Spain"
      ],
      "name": "Clara Montagut"
    },
    {
      "affiliations": [
        "Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain",
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain",
        "Institucio Catalana de Recerca i Estudis Avancats (ICREA), Barcelona, Spain"
      ],
      "name": "Eduard Batlle"
    },
    {
      "affiliations": [
        "Cancer Research Program, Hospital del Mar Research Institute (HMRIB), Barcelona, Spain"
      ],
      "name": "Alexandre Calon"
    }
  ],
  "title": "Stromal biomarker-based framework for identifying pMMR/MSS and dMMR/MSI colorectal cancers with poor outcomes and limited benefit from immunotherapy",
  "uid": "17c83d40-26dc-5ba7-9814-a6c3e280598f"
}