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.

Details

Title
Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
Author
Cazet, Aurélie S 1   VIAFID ORCID Logo  ; Hui, Mun N 2 ; Elsworth, Benjamin L 3 ; Wu, Sunny Z 1 ; Roden, Daniel 1 ; Chan, Chia-Ling 4 ; Skhinas, Joanna N 4 ; Collot, Raphaël 4 ; Yang, Jessica 4 ; Harvey, Kate 4 ; Johan, M Zahied 5 ; Cooper, Caroline 6 ; Nair, Radhika 7 ; Herrmann, David 1   VIAFID ORCID Logo  ; McFarland, Andrea 4 ; Deng, Niantao 1 ; Ruiz-Borrego, Manuel 8 ; Rojo, Federico 9 ; Trigo, José M 10 ; Bezares, Susana 11 ; Caballero, Rosalía 11 ; Lim, Elgene 12 ; Timpson, Paul 1 ; Sandra O’Toole 13 ; Watkins, D Neil 12 ; Cox, Thomas R 1   VIAFID ORCID Logo  ; Samuel, Michael S 5   VIAFID ORCID Logo  ; Martín, Miguel 14 ; Swarbrick, Alexander 1 

1  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, Australia 
2  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia; The Chris O’ Brien Lifehouse, Camperdown, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia 
3  MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK 
4  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia 
5  Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, SA, Australia; Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, SA, Australia 
6  Pathology Queensland and School of Medicine, University of Queensland, St Lucia, QLD, Australia 
7  Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, Kerala, India 
8  Department of Medical Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain 
9  Department of Pathology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain 
10  Department of Medical Oncology, Hospital Clínico Universitario Virgen de la Victoria, IBIMA, Málaga, Spain 
11  GEICAM, Spanish Breast Cancer Group, Madrid, Spain 
12  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia; St Vincent’s Clinical School, Faculty of Medicine, UNSW Sydney, Darlinghurst, NSW, Australia; St Vincent’s Hospital, Darlinghurst, NSW, Australia 
13  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Kinghorn Cancer Centre, Darlinghurst, NSW, Australia; Royal Prince Alfred Hospital, Camperdown, NSW, Australia 
14  Department of Medical Oncology, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Centro de Investigación Biomédica en Red de Oncología, CIBERONC-ISCIII, Madrid, Spain 
Pages
1-18
Publication year
2018
Publication date
Jul 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-05220-6
ProQuest document ID
2075524465
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.