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- W2891566202 abstract "e24216 Background: Paracrine Hedgehog (Hh) signalling occurs in ~30% of all triple negative breast cancers (TNBCs) and confers worse overall survival. The tumour stroma has been shown to facilitate chemoresistance in TNBC. In this study, we investigated the impact of inhibiting paracrine Hh signalling to sensitise tumours to chemotherapy. Methods: For therapeutic studies, NSG mice bearing Hh expressing TNBC (PDX) were randomised to treatment with placebo, Hh Smoothened inhibitor (LDE-225), docetaxel, and combination LDE-225 + docetaxel. Treatment continued until ethical endpoint (tumour size > 2cm, excessive toxicities or metastatic burden). At endpoint, tumours were harvested for tissue analysis. For sequencing studies, Hh expressing murine TNBCs (M6-Hh) were dissociated into neoplastic and stromal cell populations followed by bulk and single cell RNA-sequencing (SCRS). Results: RNA sequencing of neoplastic and stromal cell populations from M6-Hh tumours revealed that the former was enriched for stemness genes and the latter for genes that encode the extracellular matrix. The resulting stromal gene signature predicts worse prognosis in basal TNBC in The Cancer Genome Atlas breast cancer cohort. Using SCRS, cancer-associated fibroblasts (CAFs) were found to be the stromal cell type that respond to Hh ligand stimulation. CAF activation led to collagen remodelling and stromal FGF secretion which in turn increased the number of cancer stem cells (CSCs). CSCs inherently chemoresistant and constitute a subset of cells involved in the initial steps of metastasis. Therapeutic targeting of CAFs using an inhibitor of Smoothened (LDE-225), the key effector molecule of the Hh pathway sensitised PDXs to the effect of docetaxel. Pathway inhibition in tumour CAFs reduced FGF secretion and collagen deposition resulting in a significant reduction in tumour stem cells. This in turn translated to tumour stasis, marked reduction in metastatic burden and improved survival. Conclusions: CAFs remodel the tumour stroma to form a niche for cancer cells to evade the therapeutic effects of chemotherapy. Targeting CAFs leads to multiple downstream changes including alterations in stromal and stem cell composition which ultimately improves TNBC outcome." @default.
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- W2891566202 date "2018-05-20" @default.
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- W2891566202 title "Targeting the Hedgehog signalling pathway in triple negative breast cancer." @default.
- W2891566202 doi "https://doi.org/10.1200/jco.2018.36.15_suppl.e24216" @default.
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