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

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  • dc.contributor.author Linares Aceituno, Jenniffer Lissethe
  • dc.contributor.author Sallent-Aragay, Anna
  • dc.contributor.author Badia-Ramentol, Jordi
  • dc.contributor.author Recort-Bascuas, Alba
  • dc.contributor.author Manero Rupérez, Noemí
  • dc.contributor.author Rivas, Elisa
  • dc.contributor.author Zwick, Melissa
  • dc.contributor.author Iglesias Coma, Mar
  • dc.contributor.author Orrillo, Mayra
  • dc.contributor.author Garrido, Marta
  • dc.contributor.author Navarro Medrano, Pilar
  • dc.contributor.author Montagut Viladot, Clara
  • dc.contributor.author Calon, Alexandre
  • dc.date.accessioned 2024-02-09T09:01:06Z
  • dc.date.available 2024-02-09T09:01:06Z
  • dc.date.issued 2023
  • dc.description.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.
  • dc.description.sponsorship This work has been supported by grants from Fundación científica AECC -Asociación Española contra el Cáncer- (GCAEC20030CERV) to A.Ce., from Instituto de Salud Carlos III (ISCIII) co-funded by the European Union (CP16/00151, PI17/00211, PI20/00011; Spanish Ministry of Economy and Competitiveness) to A.Ca. and PI20/00625 to P.N., from la Caixa Foundation (LCF/PR/HR19/52160018) and MICINN (PID2020-119917RB-I00) to E.B., from Spanish Ministerio de Economia y Competitividad (MINECO) and FEDER funds (PID2019-104948RB-I00) to R.R.G. This work was supported by Grant PT20/00023, funded by Instituto de Salud Carlos III (ISCIII) and co-funded by the European Union, and the Xarxa de Bancs de tumors sponsored by Pla Director d’Oncologia de Catalunya (XBTC). A.Ca. is the recipient of funding from the Instituto de Salud Carlos III co-funded by the European Union (MS16/00151; CPII21/00012). J.L. is the recipient of a Junior Clinician fellowship from Fundación científica AECC (CLJUN19004LINA).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Linares 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/s41467-023-36334-1
  • dc.identifier.doi http://dx.doi.org/10.1038/s41467-023-36334-1
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/59049
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Commun. 2023 Feb 10;14(1):746
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-119917RB-I00
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-104948RB-I00
  • dc.rights © 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/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer microenvironment
  • dc.subject.keyword Chemotherapy
  • dc.subject.keyword Imaging techniques
  • dc.subject.keyword Predictive markers
  • dc.title Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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