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GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells Bellio, Chiara Emperador, Marta Castellano Escuder, Pol Gris Oliver, Albert Canals Suris, Francesc Sánchez Pla, Alex Serra, Violeta Zamora, Esther Arribas, Joaquin Saura, Cristina Tabernero, Josep Villanueva Cardús, Josep Institut Català de la Salut [Bellio C, Emperador M, Castellano P, Gris-Oliver A, Canals F] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Sánchez-Pla A] Genetics Microbiology and Statistics Department, Universitat de Barcelona, Barcelona, Spain. Unitat d'Estadística i Bioinformàtica, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain. [Zamora E, Saura C] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Grup de Càncer de Mama, Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Arribas J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Cancer Research Program, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain. Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. [Serra V, Tabernero J, Villanueva J] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer, Monforte de Lemos, Madrid, Spain Vall d'Hebron Barcelona Hospital Campus Marcadors bioquímics Mama - Càncer - Tractament Resistència als medicaments DISEASES::Neoplasms::Neoplasms by Site::Breast Neoplasms PHENOMENA AND PROCESSES::Physiological Phenomena::Pharmacological and Toxicological Phenomena::Pharmacological Phenomena::Drug Resistance::Drug Resistance, Neoplasm CHEMICALS AND DRUGS::Biological Factors::Biomarkers ENFERMEDADES::neoplasias::neoplasias por localización::neoplasias de la mama FENÓMENOS Y PROCESOS::fenómenos fisiológicos::fenómenos farmacológicos y toxicológicos::fenómenos farmacológicos::resistencia a medicamentos::resistencia a los antineoplásicos COMPUESTOS QUÍMICOS Y DROGAS::factores biológicos::biomarcadores Breast cancer; Drug tolerance; Secretome Cáncer de mama; Tolerancia a los fármacos; Secretoma Càncer de mama; Tolerància als fàrmacs; Secretoma Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after drug treatment. We performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. We showed that the growth differentiation factor 15 (GDF15) is a protein significantly over-secreted upon eribulin treatment. The biomarker potential of GDF15 was confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. We also found that GDF15 is required for survival of DTP cells. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function assays. Finally, we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired resistance. This research was funded by Eisai Inc. 2023-06-06T08:04:46Z 2023-06-06T08:04:46Z 2022-05-23 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Bellio C, Emperador M, Castellano P, Gris-Oliver A, Canals F, Sánchez-Pla A, et al. GDF15 Is an Eribulin Response Biomarker also Required for Survival of DTP Breast Cancer Cells. Cancers. 2022 May 23;14(10):2562. 2072-6694 https://hdl.handle.net/11351/9663 10.3390/cancers14102562 35626166 000803686000001 http://hdl.handle.net/11351/9663 eng Cancers;14(10) https://doi.org/10.3390/cancers14102562 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf MDPI Scientia