Breast cancer displays frequent intra-tumour heterogeneity as the result of genetic and non-genetic alterations that often enhances the vigour of the neoplastic population. In-depth characterization of this phenotypic and molecular diversity is paramount to improving diagnosis and the design of therapeutic strategies. Through this project, we intend to use the Hedgehog (Hh) signalling pathway as an experimental model to comprehend the complex dynamic of tumour-stroma interactions and its influence on targeted drug response.
The Hh signalling pathway has been unambiguously linked to development and aggressiveness of the challenging triple negative breast subtype (TNBC). We demonstrated a crucial paracrine mode of Hh activation in TNBC: the epithelial tumour cells secrete Hh ligand, leading to Hh pathway activation exclusively in the cancer-associated fibroblast (CAFs). Hh-activated CAFs, specifically located at the tumour margin, orchestrate an intricate crosstalk with the breast cancer (BrCa) compartment via modification of the extracellular matrix and activation of specific oncogenic pathways. This expands BrCa subpopulations are enriched for stem cell-like properties and enhance in turn tumour growth, aggressive invasion into local structures and histological dedifferentiation. Importantly, inhibition of the Hh pathway using small-molecule inhibitors of Smoothened synergies with chemotherapy to slow tumour growth and metastatic spread of a variety of TNBC models.
These findings demonstrate that Hh-activated CAFs constitute a supporting niche for breast cancer stemness in TNBC, and strongly highlight a novel rational combined approach targeting both the tumour cells and their surrounding signalling support.