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 BezaresRosalía Caballero, Elgene Lim, Paul Timpson, Sandra O’Toole, D. Neil Watkins, Thomas R. Cox, Michael S. Samuel, Miguel Martín, Alexander Swarbrick*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

95 Citations (Scopus)
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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.

Original languageEnglish
Article number2897
Number of pages18
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 24 Jul 2018

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