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Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy

Author

Listed:
  • Jenniffer Linares

    (Hospital del Mar Medical Research Institute (IMIM)
    Catalan Institute of Oncology (ICO))

  • Anna Sallent-Aragay

    (Hospital del Mar Medical Research Institute (IMIM))

  • Jordi Badia-Ramentol

    (Hospital del Mar Medical Research Institute (IMIM))

  • Alba Recort-Bascuas

    (Hospital del Mar Medical Research Institute (IMIM))

  • Ana Méndez

    (University of Oviedo)

  • Noemí Manero-Rupérez

    (Hospital del Mar Medical Research Institute (IMIM))

  • Daniele Lo Re

    (The Barcelona Institute of Science and Technology (BIST))

  • Elisa I. Rivas

    (Hospital del Mar Medical Research Institute (IMIM))

  • Marc Guiu

    (The Barcelona Institute of Science and Technology (BIST))

  • Melissa Zwick

    (Hospital del Mar Medical Research Institute (IMIM))

  • Mar Iglesias

    (Hospital del Mar Medical Research Institute (IMIM)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Carolina Martinez-Ciarpaglini

    (INCLIVA Biomedical Research Institute, University of Valencia)

  • Noelia Tarazona

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    INCLIVA Biomedical Research Institute, University of Valencia)

  • Monica Varese

    (The Barcelona Institute of Science and Technology (BIST))

  • Xavier Hernando-Momblona

    (The Barcelona Institute of Science and Technology (BIST)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Adrià Cañellas-Socias

    (The Barcelona Institute of Science and Technology (BIST)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC))

  • Mayra Orrillo

    (Medical Oncology Department, Hospital del Mar)

  • Marta Garrido

    (Hospital del Mar Medical Research Institute (IMIM))

  • Nadia Saoudi

    (Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO))

  • Elena Elez

    (Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO))

  • Pilar Navarro

    (Institute of Biomedical Research of Barcelona (IIBB-CSIC)
    Institut d’Investigacions Biomèdiques August Pi Sunyer (IDIBAPS)
    Unidad Asociada IIBB-CSIC)

  • Josep Tabernero

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Vall d’Hebron Hospital Campus and Institute of Oncology (VHIO))

  • Roger R. Gomis

    (The Barcelona Institute of Science and Technology (BIST)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Eduard Batlle

    (The Barcelona Institute of Science and Technology (BIST)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Jorge Pisonero

    (University of Oviedo)

  • Andres Cervantes

    (Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    INCLIVA Biomedical Research Institute, University of Valencia)

  • Clara Montagut

    (Hospital del Mar Medical Research Institute (IMIM)
    Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
    Medical Oncology Department, Hospital del Mar)

  • Alexandre Calon

    (Hospital del Mar Medical Research Institute (IMIM))

Abstract

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased. We determine that CT accumulation in CAFs intensifies TGF-beta activity, leading to the production of multiple factors enhancing cancer aggressiveness. We establish periostin as a stromal marker of chemotherapeutic activity intrinsically upregulated in consensus molecular subtype 4 (CMS4) tumors and highly expressed before and/or after treatment in patients unresponsive to therapy. Collectively, our study underscores the ability of CT-retaining CAFs to support cancer progression and resistance to treatment.

Suggested Citation

  • Jenniffer Linares & Anna Sallent-Aragay & Jordi Badia-Ramentol & Alba Recort-Bascuas & Ana Méndez & Noemí Manero-Rupérez & Daniele Lo Re & Elisa I. Rivas & Marc Guiu & Melissa Zwick & Mar Iglesias & C, 2023. "Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36334-1
    DOI: 10.1038/s41467-023-36334-1
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    References listed on IDEAS

    as
    1. David A. Barbie & Pablo Tamayo & Jesse S. Boehm & So Young Kim & Susan E. Moody & Ian F. Dunn & Anna C. Schinzel & Peter Sandy & Etienne Meylan & Claudia Scholl & Stefan Fröhling & Edmond M. Chan & Ma, 2009. "Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1," Nature, Nature, vol. 462(7269), pages 108-112, November.
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    3. Elisa I. Rivas & Jenniffer Linares & Melissa Zwick & Andrea Gómez-Llonin & Marc Guiu & Anna Labernadie & Jordi Badia-Ramentol & Anna Lladó & Lídia Bardia & Iván Pérez-Núñez & Carolina Martínez-Ciarpag, 2022. "Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
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