Project Summary

Basal cell carcinoma (BCC) is the most common tumor in humans. Almost all BCC show a pathological activation of the Hedgehog/Patched (Hh/Ptch) signaling cascade that in most cases is caused by inactivating mutations in the tumor suppressor gene Ptch.

In conditional Ptchflox/floxERT2+/- knock-out mice, basal cell carcinoma (BCC) regress with time and show a more differentiated phenotype. Interestingly, this is accompanied by upregulation of Wnt5a in the tumor-stroma. In vitro experiments revealed that Wnt5a is upregulated in tumor-adjacent macrophages by soluble signals derived from BCC cells. In turn Wnt5a induces the expression of the differentiation marker K10 in tumor cells, which is mediated by Wnt/Ca2+ signaling in a CaMKII-dependent manner. These data suggest that, in contrast to many other tumors, Wnt5a upregulation in the stroma of BCC is a tumor-defense mechanism leading to BCC regression and differentiation.   

The current aim is to verify the role of Wnt5a in differentiation and regression of BCC in vivo. Wnt5a levels will be either decreased or increased in BCC-bearing skin. In addition, we will a) investigate the role of Ca2+ and CaMKII-dependent Wnt/Ca2+ signaling in BCC-defense-mechanisms, b) determine the Wnt5a receptor responsible for activation of CaMKII-dependent Wnt/Ca2+ signaling in BCC, c) identify the soluble signals of BCC cells responsible for induction of Wnt5a in tumor-associated macrophages and d) identify other components of the Wnt signaling cascade involved in BCC regression.