The overarching focus of cancer biology and therapy for the past decades has been on genetic and epigenetic alterations of cancer cells, seeking to understand the basis for malignancy. However, there is now overwhelming evidence that the behaviour of tumorigenic cells is also highly influenced by their microenvironment.
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 accelerates tumour growth and is associated with a poor outcome in terms of metastasis and breast cancer-related death. We show that inhibition of the Hh pathway using Vismodegib, a potent orally bioavailable small-molecule inhibitor of Smoothened, reduced tumour growth and improved median survival in multiple mouse models. Importantly, 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. Ongoing transcriptome profiling by next-generation sequencing of epithelial and stromal fractions from TNBC tumours will reveal insights into the Hh-mediated loop of activation within the tumour microenvironment.
This work has important translational application. Our findings strongly suggest a paracrine requirement for the Hh pathway in TNBC and support a novel therapeutic approach directed at the “genetically stable” CAFs in the microenvironment. In this context, dissecting the underlying biology and the fundamental molecular mechanisms of paracrine Hh signalling in mouse models and human tumours would highlight appropriate novel combination therapies.