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 and Alexander Swarbrick ()
Additional contact information
Aurélie S. Cazet: Garvan Institute of Medical Research
Mun N. Hui: Garvan Institute of Medical Research
Benjamin L. 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: SA Pathology and the University of South Australia
Caroline Cooper: 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 Ruiz-Borrego: Hospital Universitario Virgen del Rocío
Federico Rojo: Hospital Universitario Fundación Jiménez Díaz
José M. Trigo: IBIMA
Susana Bezares: Spanish Breast Cancer Group
Rosalía Caballero: Spanish Breast Cancer Group
Elgene Lim: Garvan Institute of Medical Research
Paul Timpson: Garvan Institute of Medical Research
Sandra O’Toole: Garvan Institute of Medical Research
D. Neil Watkins: Garvan Institute of Medical Research
Thomas R. Cox: Garvan Institute of Medical Research
Michael S. Samuel: SA Pathology and the University of South Australia
Miguel Martín: Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII
Alexander Swarbrick: Garvan Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05220-6

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