Cazet, Aurélie SHui, Mun NElsworth, Benjamin LWu, Sunny ZRoden, DanielChan, Chia-LingSkhinas, Joanna NCollot, RaphaëlYang, JessicaHarvey, KateJohan, M ZahiedCooper, CarolineNair, RadhikaHerrmann, DavidMcFarland, AndreaDeng, NiantaoRuiz-Borrego, ManuelRojo, FedericoTrigo, José MBezares, SusanaCaballero, RosalíaLim, ElgeneTimpson, PaulO'Toole, SandraWatkins, D NeilCox, Thomas RSamuel, Michael SMartín, MiguelSwarbrick, Alexander2023-01-252023-01-252018-07-24http://hdl.handle.net/10668/12750The 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.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AdultAgedAnilidesAnimalsAntineoplastic Combined Chemotherapy ProtocolsBiphenyl CompoundsCell Line, TumorDocetaxelDrug Resistance, NeoplasmFemaleHumansMice, Inbred NODMice, KnockoutMice, SCIDMiddle AgedNeoplastic Stem CellsPyridinesTreatment OutcomeTriple Negative Breast NeoplasmsXenograft Model Antitumor Assaysresearch article30042390open access10.1038/s41467-018-05220-62041-1723PMC6057940https://www.nature.com/articles/s41467-018-05220-6.pdfhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057940/pdf