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Nat Commun. 2018 Jul 24;9(1):2897. doi: 10.1038/s41467-018-05220-6.

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

Cazet AS1,2,3, Hui MN1,2,4,5, Elsworth BL6, Wu SZ1,2,3, Roden D1,2,3, Chan CL1,2, Skhinas JN1,2, Collot R1,2, Yang J1,2, Harvey K1,2, Johan MZ7,8, Cooper C9, Nair R10, Herrmann D1,2,3, McFarland A1,2, Deng N1,2,3, Ruiz-Borrego M11, Rojo F12, Trigo JM13, Bezares S14, Caballero R14, Lim E1,2,3,15, Timpson P1,2,3, O'Toole S1,2,5, Watkins DN1,2,3,15, Cox TR1,2,3, Samuel MS7,8, Martín M16, Swarbrick A17,18,19.

Author information

1
Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.
2
The Kinghorn Cancer Centre, Darlinghurst, NSW, 2010, Australia.
3
St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, 2010, Australia.
4
The Chris O' Brien Lifehouse, Camperdown, NSW, 2050, Australia.
5
Royal Prince Alfred Hospital, Camperdown, NSW, 2050, Australia.
6
MRC Integrative Epidemiology Unit, University of Bristol, Oakfield House, Bristol, BS8 2BN, UK.
7
Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, 5000, Australia.
8
Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, SA, 5000, Australia.
9
Pathology Queensland and School of Medicine, University of Queensland, St Lucia, QLD, 4006, Australia.
10
Rajiv Gandhi Centre for Biotechnology, Thycaud Post, Poojappura, Thiruvananthapuram, Kerala, 695014, India.
11
Department of Medical Oncology, Hospital Universitario Virgen del Rocío, 41013, Sevilla, Spain.
12
Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, 28040, Madrid, Spain.
13
Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, IBIMA, 29010, Málaga, Spain.
14
GEICAM, Spanish Breast Cancer Group, Madrid, 28703, Spain.
15
St Vincent's Hospital, 2010, Darlinghurst, NSW, Australia.
16
Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, 28040, Madrid, Spain.
17
Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. a.swarbrick@garvan.org.au.
18
The Kinghorn Cancer Centre, Darlinghurst, NSW, 2010, Australia. a.swarbrick@garvan.org.au.
19
St Vincent's Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, 2010, Australia. a.swarbrick@garvan.org.au.

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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