The importance of the tumour microenvironment in dictating treatment response is increasingly evident. This research project combines clinically relevant models of primary breast cancers and uses cutting-edge technology to investigate the influence of the heterogeneous tumour stroma in the challenging triple negative breast subtype (TNBC), for which new-targeted therapeutic agents are urgently needed. We focus on the paracrine Hedgehog (Hh) signalling pathway, which has been unambiguously linked to development and aggressiveness of 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. Hh signalling occurs exclusively in a small number of stromal cells immediately adjacent to the tumour. By using Single Cell Gene Expression technology as well as in vitro co-culture models, we collected evidence suggesting that cancer associated fibroblasts (CAFs) are the critical cell type in paracrine Hh signalling. Transcriptome profiling by next-generation sequencing of epithelial and stromal fractions from TNBC tumours have also revealed insights into the Hh-mediated loop of activation. Stromal cells orchestrate an intricate crosstalk with the breast cancer (BrCa) compartment via modification of the extracellular matrix. In parallel, this expands BrCa subpopulations are enriched for stem cell-like properties.
This work has important translational application. 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. Importantly, we recently showed that inhibition of the Hh pathway using Vismodegib and Sonidegib, two potent orally bioavailable small-molecule inhibitor of Smoothened, synergies with chemotherapy to slow tumour growth and metastatic spread of Patient Derivated Xenografts.