期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05220-6
关键词
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资金
- National Health and Medical Research Council (NHMRC) of Australia
- McMurtrie family
- Estate of the late RT Hall
- NHMRC
- 2013 Pfizer Australia Cancer Research Grant
- Australia Postgraduate Award
- Sydney Catalyst Top-Up Scholarship
- Sydney Breast Cancer Foundation Fellowship
- Australian Research Council
- Cancer Council South Australia
- Royal Adelaide Hospital
- Len Ainsworth Research Fellowship
- NBCF practitioner fellowship
- Sydney Breast Cancer Foundation
- Tag family
- ICAP
- O'Sullivan family
- estate of the late Kylie Sinclair
- Novartis
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 xeno-grafts 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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