TY - JOUR
T1 - Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
AU - Cazet, Aurélie S.
AU - Hui, Mun N.
AU - Elsworth, Benjamin L.
AU - Wu, Sunny Z.
AU - Roden, Daniel
AU - Chan, Chia Ling
AU - Skhinas, Joanna N.
AU - Collot, Raphaël
AU - Yang, Jessica
AU - Harvey, Kate
AU - Johan, M. Zahied
AU - Cooper, Caroline
AU - Nair, Radhika
AU - Herrmann, David
AU - McFarland, Andrea
AU - Deng, Niantao
AU - Ruiz-Borrego, Manuel
AU - Rojo, Federico
AU - Trigo, José M.
AU - Bezares, Susana
AU - Caballero, Rosalía
AU - Lim, Elgene
AU - Timpson, Paul
AU - O’Toole, Sandra
AU - Watkins, D. Neil
AU - Cox, Thomas R.
AU - Samuel, Michael S.
AU - Martín, Miguel
AU - Swarbrick, Alexander
PY - 2018/7/24
Y1 - 2018/7/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85050625637&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05220-6
DO - 10.1038/s41467-018-05220-6
M3 - Article (Academic Journal)
C2 - 30042390
AN - SCOPUS:85050625637
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 2897
ER -