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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Cazet AS,Hui MN,Elsworth BL,Wu SZ,Roden D,Chan CL,Skhinas JN,Collot R,Yang J,Harvey K,Johan MZ,Cooper C,Nair R,Herrmann D,McFarland A,Deng N,Ruiz-Borrego M,Rojo F,Trigo JM,Bezares S,Caballero R,Lim E,Timpson Pdoi
10.1038/s41467-018-05220-6subject
Has Abstractpub_date
2018-07-24 00:00:00pages
2897issue
1issn
2041-1723pii
10.1038/s41467-018-05220-6journal_volume
9pub_type
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