Targeted therapy modulates the secretome of cancer-associated fibroblasts to induce resistance in HER2-positive breast cancer

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• dc.contributor.author Luque, Melani
• dc.contributor.author Sanz Álvarez, Marta
• dc.contributor.author Santamaría, Andrea
• dc.contributor.author Zazo, Sandra
• dc.contributor.author Cristóbal, Ion
• dc.contributor.author Fuente, Lorena de la
• dc.contributor.author Mínguez, Pablo
• dc.contributor.author Eroles, Pilar
• dc.contributor.author Rovira Guerín, Ana
• dc.contributor.author Albanell Mestres, Joan
• dc.contributor.author Madoz-Gúrpide, Juan
• dc.contributor.author Rojo, Federico
• dc.date.accessioned 2022-09-27T06:07:04Z
• dc.date.available 2022-09-27T06:07:04Z
• dc.date.issued 2021
• dc.description.abstract The combination of trastuzumab plus pertuzumab plus docetaxel as a first-line therapy in patients with HER2-positive metastatic breast cancer has provided significant clinical benefits compared to trastuzumab plus docetaxel alone. However, despite the therapeutic success of existing therapies targeting HER2, tumours invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance, so that specific therapeutic strategies can be developed to provide improved efficacy. It is well known that the tumour microenvironment (TME) has a significant impact on cancer behaviour. Cancer-associated fibroblasts (CAFs) are essential components of the tumour stroma that have been linked to acquired therapeutic resistance and poor prognosis in breast cancer. For this reason, it would be of interest to identify novel biomarkers in the tumour stroma that could emerge as therapeutic targets for the modulation of resistant phenotypes. Conditioned medium experiments carried out in our laboratory with CAFs derived from HER2-positive patients showed a significant capacity to promote resistance to trastuzumab plus pertuzumab therapies in two HER2-positive breast cancer cell lines (BCCLs), even in the presence of docetaxel. In order to elucidate the components of the CAF-conditioned medium that may be relevant in the promotion of BCCL resistance, we implemented a multiomics strategy to identify cytokines, transcription factors, kinases and miRNAs in the secretome that have specific targets in cancer cells. The combination of cytokine arrays, label-free LC-MS/MS quantification and miRNA analysis to explore the secretome of CAFs under treatment conditions revealed several up- and downregulated candidates. We discuss the potential role of some of the most interesting candidates in generating resistance in HER2-positive breast cancer.
• dc.format.mimetype application/pdf
• dc.identifier.citation Luque M, Sanz-Álvarez M, Santamaría A, Zazo S, Cristóbal I, de la Fuente L, Mínguez P, Eroles P, Rovira A, Albanell J, Madoz-Gúrpide J, Rojo F. Targeted therapy modulates the secretome of cancer-associated fibroblasts to induce resistance in HER2-positive breast cancer. Int J Mol Sci. 2021 Dec 10;22(24):13297. DOI: 10.3390/ijms222413297
• dc.identifier.doi http://dx.doi.org/10.3390/ijms222413297
• dc.identifier.issn 1422-0067
• dc.identifier.uri http://hdl.handle.net/10230/54175
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Int J Mol Sci. 2021 Dec 10;22(24):13297
• dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri https://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword HER2-positive
• dc.subject.keyword Breast cancer
• dc.subject.keyword Cancer-associated fibroblast
• dc.subject.keyword Label-free proteomics
• dc.subject.keyword miRNA
• dc.subject.keyword Resistance
• dc.subject.keyword Targeted therapy
• dc.subject.keyword Trastuzumab
• dc.subject.keyword Tumour microenvironment
• dc.title Targeted therapy modulates the secretome of cancer-associated fibroblasts to induce resistance in HER2-positive breast cancer
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion