RT Journal Article
T1 Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer.
A1 Cazet, Aurélie S
A1 Hui, Mun N
A1 Elsworth, Benjamin L
A1 Wu, Sunny Z
A1 Roden, Daniel
A1 Chan, Chia-Ling
A1 Skhinas, Joanna N
A1 Collot, Raphaël
A1 Yang, Jessica
A1 Harvey, Kate
A1 Johan, M Zahied
A1 Cooper, Caroline
A1 Nair, Radhika
A1 Herrmann, David
A1 McFarland, Andrea
A1 Deng, Niantao
A1 Ruiz-Borrego, Manuel
A1 Rojo, Federico
A1 Trigo, José M
A1 Bezares, Susana
A1 Caballero, Rosalía
A1 Lim, Elgene
A1 Timpson, Paul
A1 O'Toole, Sandra
A1 Watkins, D Neil
A1 Cox, Thomas R
A1 Samuel, Michael S
A1 Martín, Miguel
A1 Swarbrick, Alexander
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.
YR 2018
FD 2018-07-24
LK http://hdl.handle.net/10668/12750
UL http://hdl.handle.net/10668/12750
LA en
DS RISalud
RD Apr 13, 2025