%0 Journal Article
%A Cazet, Aurélie S
%A Hui, Mun N
%A Elsworth, Benjamin L
%A Wu, Sunny Z
%A Roden, Daniel
%A Chan, Chia-Ling
%A Skhinas, Joanna N
%A Collot, Raphaël
%A Yang, Jessica
%A Harvey, Kate
%A Johan, M Zahied
%A Cooper, Caroline
%A Nair, Radhika
%A Herrmann, David
%A McFarland, Andrea
%A Deng, Niantao
%A Ruiz-Borrego, Manuel
%A Rojo, Federico
%A Trigo, José M
%A Bezares, Susana
%A Caballero, Rosalía
%A Lim, Elgene
%A Timpson, Paul
%A O'Toole, Sandra
%A Watkins, D Neil
%A Cox, Thomas R
%A Samuel, Michael S
%A Martín, Miguel
%A Swarbrick, Alexander
%T Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.
%D 2018
%U http://hdl.handle.net/10668/12750
%X 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.
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