1) Mechanism and function of cancer-associated fibroblast (CAF) and pericyte activation during breast cancer progression
There is now extensive functional evidence implicating a role for cancer-associated fibroblasts (CAFs) in tumour progression, either by their ability to deposit and remodel the extracellular matrix, by the secretion of pro-tumourigenic factors or by modulation of the immune compartment.
Our laboratory has been addressing the mechanisms that underpin fibroblast heterogeneity in breast cancers. First, by gene expression profiling of aggressive and non-aggressive tumours, we have identified Wnt7a as a key tumour cell-secreted factor that promotes both fibroblast recruitment and activation in three-dimensional in-vitro assays and in vivo studies. Functionally, high Wnt7a expression in tumour cells promotes metastasis in vivo and, in human breast cancers, correlates with a desmoplastic, poor-prognosis stroma accompanied by high TGFbeta pathway activation in fibroblasts and reduced patient survival (Avgustinova et al., 2016).
Currently, we are exploring the recruitment of CAF subsets during the establishment of a favourable metastatic microenvironment and the role of CAFs in driving an immune suppressive microenvironment in the tumour that underpins the clinical observation that breast cancers are often refractory to immunotherapy.
Pericytes are a mesenchymal cell population that function to stabilise quiescent resting vessels; however, their role in both developmental and tumour angiogenesis is less well understood. Endosialin (also known as CD248) is a large transmembrane glycoprotein that was reported originally to be one of the most highly upregulated genes in the tumour vasculature compared to normal vasculature.
Our laboratory was the first to demonstrate that endosialin is not expressed on endothelial cells but on the activated pericytes (MacFadyen et al., 2005; MacFadyen et al. 2007; Simonavicius 2010) where it binds to a vascular basement membrane components and regulators of vascular branching (Simonavicius et al., 2012).
In collaboration with Hellmut Augustin's laboratory (DKFZ Heidelberg) we have demonstrated that endosialin-positive pericytes actively facilitate metastatic spread by promoting tumour cell intravasation and subsequent dissemination (Viski et al., 2016).
Currently, we are exploring the utility of targeting fibroblast/pericyte activation receptors upregulated in the tumour stroma focusing initially on endosialin (see above) and the endocytic recycling receptor Endo180 (MRC2, uPARAP).
Endo180 is predominantly expressed by stromal fibroblasts, functioning as a pro-migratory, novel collagen uptake receptor (Wienke et al., 2003; Sturge et al., 2006; Huijbers et al., 2010). More recently, we demonstrated that genetic deletion of Endo180 severely impairs colonisation of tumour cells at the metastatic sites.