The importance of the tumour microenvironment in dictating treatment response is increasingly evident. We focus on the paracrine Hedgehog (Hh) signalling pathway, which has been unambiguously linked to development and aggressiveness of the triple negative breast cancer subtype (TNBC).
Hh ligand overexpression by cancerous cells is an early event in mammary carcinogenesis, strongly associated with a basal-like phenotype and poor outcome in terms of metastasis and breast cancer-related death. By using Single Cell Gene Expression technology as well as in vitro co-culture models, we collect evidence suggested that Hh signalling occurs exclusively in a small number of stromal fibroblasts, immediately adjacent to the tumour. Hh signalling to cancer-associated fibroblasts (CAFs) drives the expression of a suite of genes responsible for remodelling the ECM. It also orchestrates an intricate crosstalk with the breast cancer (BrCa) compartment, promoting tumour growth, stemness of the BrCa cells, aggressive invasion into local structures and histological dedifferentiation.
Thus, our data demonstrate that Hh-activated CAFs constitute a supporting niche for breast cancer stemness, and strongly support a novel therapeutic approach for TNBC by targeting Hh oncogenic signalling in the “genetically stable” stromal population. We recently explored the clinical potential for Smoothened inhibitors in TNBC. Combination-based therapy using orally bioavailable small-molecule inhibitor of Smoothened with docetaxel results in significant retardation in tumour growth and metastatic spread of diverse murine and Patient Derivated Xenografts.