β-catenin/Wnt signaling in non-melanoma skin cancer

URPP Fellows: Virginia Cecconi, Tomas Valenta

Squamous cell carcinoma (SCC) is one of the most frequent non-melanoma skin cancers that often occurs in sun-exposed regions of the skin. SCC originates in keratinocytes and is induced by UV-light. SCC is often cured surgically, but it relapses in 8% of patients and ca. 5% of patients develop metastasis with poor prognosis.

One of key signalling mechanism promoting the development of SCC is driven by activating Ras mutation. Besides Ras pathway, recently, canonical Wnt signalling was shown to be important for the initiation and development of SCC in some mouse models. The key component of the canonical Wnt pathway is b-catenin, which is often found to be aberrantly active in various types of cancer. b-catenin is the central regulator of gene expression by providing transcriptional activity to TCF/LEF transcription factors, which on their own possess only limited ability to regulate transcription. b-catenin does not contain any specific transactivation domains, but rather serves as a scaffolding protein targeting specific transcriptional co-activators to Wnt-responsive genes and thus changing their transcriptional status. The signaling activity of b-catenin depends on different regions within its polypeptide sequence, which are crucial for the recruitment of different transcriptional activators. Besides its signaling function, b-catenin serves as an important component in the cadherin-based cell-cell adhesion system that is required for the structural integrity and function of epithelia. The dual nature of b-catenin makes it difficult to specifically study its signaling functions in epithelial tissues as skin epidermis.

Basal cell carcinoma represent another non-melanoma skin cancer originated from epidermis, but in contrast to SCC it develops from most deep epidermal layer. Whereas the role of Hedgehog signaling for development of BCC is well documented, the possible involvement of Wnt signaling for BCC initiation and progression is only poorly understood, although there is certain evidence indicating the role of Wnt pathway during BCC growth.

Within the proposed project we aim to address the role of the b-catenin transcriptional output for the development of non-melanoma skin cancer (SCC and BCC) with a special focus on its role in the modulation of immune responses against developing tumors. Another important aspect of our work will be directed to understand how Wnt signaling modulates Ras (in SCC), respectively Hedgehog (in BCC) outputs and vice versa. Such a modulation or crosstalk might be relevant also in other type of cancer.

To investigate the roles of b-catenin in SCC or BCC development we will combine specific b-catenin mutant mouse strains we generated with a genetically defined SCC or BCC model. We have established two models for SCC (DMBA/TPA (Abel et al., 2009) and UV-inducible K14-HPV8E6 (Schaper et al., 2005)) and one RU486-inducible model for BCC (K5-CrePR x Ptch1fl/fl) (Kasper et al., 2011).

In our model animals the only source of b-catenin in developing SCC or BCC will be provided by the mutant b-catenin alleles, and thus we can determine the specific contribution of individual b-catenin transcriptional co-activators to the initiation and progression of non-melanoma skin cancers.  Detailed analyses of SCC and BCC with impaired Wnt/b-catenin signaling may reveal whether Wnt/b-catenin activity cannot only affect tumor development but even immune responses against SCC or BCC. Our results may help to establish better and efficient therapeutic approaches for treatment of non-melanoma skin cancer combining both immunomodulation and altering Wnt/b-catenin signaling together with other signaling pathways.