Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer

TLDR

Stromal cell recruitment and activation in carcinomas remain poorly understood, hindering targeted anti‑stromal therapy development. Hedgehog ligand from tumor cells reprograms CAFs to support chemo‑resistant CSCs through FGF5 expression and fibrillar collagen production in TNBC mouse models. SMOi treatment of TNBC tumors downregulates CSC markers, restores docetaxel sensitivity, improves survival and reduces metastasis, and in a phase I trial 3 of 12 metastatic patients achieved clinical benefit—including a complete response—highlighting Hedgehog‑CAF signaling as a novel target for overcoming chemoresistance.

Abstract

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.