Linares Aceituno, Jenniffer LissetheSallent-Aragay, AnnaBadia-Ramentol, JordiRecort-Bascuas, AlbaManero Rupérez, NoemíRivas, ElisaZwick, MelissaIglesias Coma, MarOrrillo, MayraGarrido, MartaNavarro Medrano, PilarMontagut Viladot, ClaraCalon, Alexandre2024-02-092024-02-092023Linares J, Sallent-Aragay A, Badia-Ramentol J, Recort-Bascuas A, Méndez A, Manero-Rupérez N, et al. Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy. Nat Commun. 2023 Feb 10;14(1):746. DOI: 10.1038/s41467-023-36334-12041-1723http://hdl.handle.net/10230/59049A 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.application/pdfeng© 2023, The Author(s).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/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41467-023-36334-1Cancer microenvironmentChemotherapyImaging techniquesPredictive markersinfo:eu-repo/semantics/openAccess