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Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer

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.

Type Journal
ISBN 2041-1723
Authors Cazet, A. S.; Hui, M. N.; Elsworth, B. L.; Wu, S. Z.; Roden, D.; Chan, C. L.; Skhinas, J. N.; Collot, R.; Yang, J.; Harvey, K.; Johan, M. Z.; Cooper, C.; Nair, R.; Herrmann, D.; McFarland, A.; Deng, N.; Ruiz-Borrego, M.; Rojo, F.; Trigo, J. M.; Bezares, S.; Caballero, R.; Lim, E.; Timpson, P.; O'Toole, S.; Watkins, D. N.; Cox, T. R.; Samuel, M. S.; Martin, M.; Swarbrick, A.
Responsible Garvan Author Dr Aurelie Cazet
Publisher Name Nature Communications
Published Date 2018-07-24
Published Volume 9
Published Issue 1
Published Pages 2897
Status Always Electronic
DOI 10.1038/s41467-018-05220-6
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/30042390
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/14637