Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
Aurélie S Cazet, Mun N Hui, Benjamin L Elsworth, Sunny Z Wu, Daniel Roden, Chia-Ling Chan, Joanna N Skhinas, Raphaël Collot, Jessica Yang, Kate Harvey, M Zahied Johan, Caroline Cooper, Radhika Nair, David Herrmann, Andrea McFarland, Niantao Deng, Manuel Ruiz-Borrego, Federico Rojo, José M Trigo, Susana Bezares, Rosalía Caballero, Elgene Lim, Paul Timpson, Sandra O'Toole, D Neil Watkins, Thomas R Cox, Michael S Samuel, Miguel Martín, Alexander Swarbrick, Aurélie S Cazet, Mun N Hui, Benjamin L Elsworth, Sunny Z Wu, Daniel Roden, Chia-Ling Chan, Joanna N Skhinas, Raphaël Collot, Jessica Yang, Kate Harvey, M Zahied Johan, Caroline Cooper, Radhika Nair, David Herrmann, Andrea McFarland, Niantao Deng, Manuel Ruiz-Borrego, Federico Rojo, José M Trigo, Susana Bezares, Rosalía Caballero, Elgene Lim, Paul Timpson, Sandra O'Toole, D Neil Watkins, Thomas R Cox, Michael S Samuel, Miguel Martín, Alexander Swarbrick
Abstract
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.
Conflict of interest statement
Novartis funded a part of the study. The authors declare no other competing interests.
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References
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