PT  - JOURNAL ARTICLE
AU  - Aurélie S. Cazet
AU  - Mun N. Hui
AU  - Benjamin L. Elsworth
AU  - Sunny Z. Wu
AU  - Daniel Roden
AU  - Chia-Ling Chan
AU  - Joanna N. Skhinas
AU  - Raphaël Collot
AU  - Jessica Yang
AU  - Kate Harvey
AU  - M. Zahied Johan
AU  - Caroline Cooper
AU  - Radhika Nair
AU  - David Herrmann
AU  - Andrea McFarland
AU  - Nian-Tao Deng
AU  - Manuel Ruiz-Borrego
AU  - Federico Rojo
AU  - José M. Trigo
AU  - Susana Bezares
AU  - Rosalía Caballero
AU  - Elgene Lim
AU  - Paul Timpson
AU  - Sandra O’Toole
AU  - D. Neil Watkins
AU  - Thomas R. Cox
AU  - Michael Samuel
AU  - Miguel Martín
AU  - Alexander Swarbrick
TI  - Targeting stromal remodeling and cancer stem cell plasticity to overcome chemoresistance in triple negative breast cancer
AID  - 10.1101/215954
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 215954
4099  - http://biorxiv.org/content/early/2017/11/08/215954.short
4100  - http://biorxiv.org/content/early/2017/11/08/215954.full
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), Hh ligand produced by neoplastic cells reprogrammed cancer-associated fibroblast (CAF) gene expression, driving tumor growth and metastasis. Hh-activated CAFs upregulated expression of FGF5 and production of fibrillar collagen, leading to FGFR and FAK activation in adjacent neoplastic cells, which then acquired a stem-like, drug-resistant phenotype. Treatment with smoothened inhibitors (SMOi) reversed these phenotypes. Stromal treatment of TNBC patient-derived xenograft (PDX) models with SMOi downregulated the expression of cancer stem cell markers and sensitized 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. Markers of pathway activity correlated with response. These studies identify Hh signaling to CAFs as a novel mediator of cancer stem cell plasticity and an exciting new therapeutic target in TNBC.SIGNIFICANCE Compared to other breast cancer subtypes, TNBCs are associated with significantly worse patient outcomes. Standard of care systemic treatment for patients with non-BRCA1/2 positive TNBC is cytotoxic chemotherapy. However, the failure of 70% of treated TNBCs to attain complete pathological response reflects the relative chemoresistance of these tumors. New therapeutic strategies are needed to improve patient survival and quality of life. Here, we provide new insights into the dynamic interactions between heterotypic cells within a tumor. Specifically, we establish the mechanisms by which CAFs define cancer cell phenotype and demonstrate that the bidirectional CAF-cancer cell crosstalk can be successfully targeted in mice and humans using anti-stromal therapy.