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

Aurélie Cazet(Garvan Institute of Medical Research), Mun N. Hui(Garvan Institute of Medical Research), Benjamin Elsworth(University of Bristol), Sunny Z. Wu(Garvan Institute of Medical Research), Daniel Roden(Garvan Institute of Medical Research), Chia-Ling Chan(Garvan Institute of Medical Research), Joanna N. Skhinas(Garvan Institute of Medical Research), Raphaël Collot(Garvan Institute of Medical Research), Jessica Yang(Garvan Institute of Medical Research), Kate Harvey(Garvan Institute of Medical Research), M. Zahied Johan(South Australia Pathology), Caroline Cooper(The University of Queensland), Radhika Nair(Rajiv Gandhi Centre for Biotechnology), David Herrmann(Garvan Institute of Medical Research), Andrea McFarland(Garvan Institute of Medical Research), Niantao Deng(Garvan Institute of Medical Research), Manuel Ruíz‐Borrego(Hospital Universitario Virgen del Rocío), Federico Rojo(Hospital Universitario Fundación Jiménez Díaz), José Trigo(Hospital Clínico Universitario Virgen de la Victoria), Susana Bezares(GEICAM – Spanish Breast Cancer Group), Rosalía Caballero(GEICAM – Spanish Breast Cancer Group), Elgene Lim(Garvan Institute of Medical Research), Paul Timpson(Garvan Institute of Medical Research), Sandra O’Toole(The Kinghorn Cancer Centre), D. Neil Watkins(Garvan Institute of Medical Research), Thomas R. Cox(Garvan Institute of Medical Research), Michael S. Samuel(South Australia Pathology), Miguel Martín(Instituto de Salud Carlos III), Alexander Swarbrick(Garvan Institute of Medical Research)
Nature Communications
July 18, 2018
10.1038/s41467-018-05220-6
Cited by 440Open Access
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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.

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