RT Journal Article T1 Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. A1 Cazet, Aurélie S A1 Hui, Mun N A1 Elsworth, Benjamin L A1 Wu, Sunny Z A1 Roden, Daniel A1 Chan, Chia-Ling A1 Skhinas, Joanna N A1 Collot, Raphaël A1 Yang, Jessica A1 Harvey, Kate A1 Johan, M Zahied A1 Cooper, Caroline A1 Nair, Radhika A1 Herrmann, David A1 McFarland, Andrea A1 Deng, Niantao A1 Ruiz-Borrego, Manuel A1 Rojo, Federico A1 Trigo, José M A1 Bezares, Susana A1 Caballero, Rosalía A1 Lim, Elgene A1 Timpson, Paul A1 O'Toole, Sandra A1 Watkins, D Neil A1 Cox, Thomas R A1 Samuel, Michael S A1 Martín, Miguel A1 Swarbrick, Alexander AB The cellular and molecular basis of stromal cell recruitment, activation and crosstalk in carcinomas is poorly understood, limiting the development of targeted anti-stromal therapies. In mouse models of triple negative breast cancer (TNBC), Hedgehog ligand produced by neoplastic cells reprograms cancer-associated fibroblasts (CAFs) to provide a supportive niche for the acquisition of a chemo-resistant, cancer stem cell (CSC) phenotype via FGF5 expression and production of fibrillar collagen. Stromal treatment of patient-derived xenografts with smoothened inhibitors (SMOi) downregulates CSC markers expression and sensitizes tumors to docetaxel, leading to markedly improved survival and reduced metastatic burden. In the phase I clinical trial EDALINE, 3 of 12 patients with metastatic TNBC derived clinical benefit from combination therapy with the SMOi Sonidegib and docetaxel chemotherapy, with one patient experiencing a complete response. These studies identify Hedgehog signaling to CAFs as a novel mediator of CSC plasticity and an exciting new therapeutic target in TNBC. YR 2018 FD 2018-07-24 LK http://hdl.handle.net/10668/12750 UL http://hdl.handle.net/10668/12750 LA en DS RISalud RD Apr 12, 2025