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Type: Journal article
Title: Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer
Author: Cazet, A.
Hui, M.
Elsworth, B.
Wu, S.
Roden, D.
Chan, C.
Skhinas, J.
Collot, R.
Yang, J.
Harvey, K.
Johan, M.
Cooper, C.
Nair, R.
Herrmann, D.
McFarland, A.
Deng, N.
Ruiz-Borrego, M.
Rojo, F.
Trigo, J.
Bezares, S.
et al.
Citation: Nature Communications, 2018; 9(1):2897N-1-2897N-18
Publisher: Nature Publishing Group
Issue Date: 2018
ISSN: 2041-1723
Statement of
Aurélie S. Cazet, Mun N. Hui, Benjamin L. Elsworth, Sunny Z. Wu, Daniel Roden ... Michael S. Samuel ... et al.
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.
Keywords: Xenograft Model Antitumor Assays
Rights: © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit licenses/by/4.0/.
RMID: 0030095358
DOI: 10.1038/s41467-018-05220-6
Appears in Collections:Medicine publications

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