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

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, Carolina Martinez-Ciarpaglini, Noelia Tarazona, Monica Varese, Xavier Hernando-Momblona, Adrià Cañellas-Socias, Mayra Orrillo, Marta Garrido, Nadia Saoudi, Elena Elez, Pilar Navarro, Josep Tabernero, Roger R. Gomis, Eduard Batlle, Jorge Pisonero, Andres Cervantes, Clara Montagut and Alexandre Calon ()
Additional contact information
Jenniffer Linares: Hospital del Mar Medical Research Institute (IMIM)
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)
Carolina Martinez-Ciarpaglini: INCLIVA Biomedical Research Institute, University of Valencia
Noelia Tarazona: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Monica Varese: The Barcelona Institute of Science and Technology (BIST)
Xavier Hernando-Momblona: The Barcelona Institute of Science and Technology (BIST)
Adrià Cañellas-Socias: The Barcelona Institute of Science and Technology (BIST)
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)
Josep Tabernero: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Roger R. Gomis: The Barcelona Institute of Science and Technology (BIST)
Eduard Batlle: The Barcelona Institute of Science and Technology (BIST)
Jorge Pisonero: University of Oviedo
Andres Cervantes: Centro de Investigación Biomédica en Red de Cáncer (CIBERONC)
Clara Montagut: Hospital del Mar Medical Research Institute (IMIM)
Alexandre Calon: Hospital del Mar Medical Research Institute (IMIM)

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36334-1

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