β-catenin/Wnt signaling in non-melanoma skin cancer and colon 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 can relapse and ca. 5% of patients develop metastasis with poor prognosis.
One of key signaling mechanism promoting the development of SCC is driven by activating Ras mutation. Besides Ras pathway, recently, canonical Wnt signaling 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 β-catenin, which is often found to be aberrantly active in various types of cancer. β-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. β-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 β-catenin depends on different regions within its polypeptide sequence, which are crucial for the recruitment of different transcriptional activators. Besides its signaling function, β-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 β-catenin makes it difficult to specifically study its signaling functions in epithelial tissues as skin epidermis. Within the proposed project we aim to address the role of the β-catenin transcriptional output for the development of non-melanoma skin cancer (SCC) and colon cancer.
In our model animals, the only source of β-catenin in developing SCC or BCC will be provided by the mutant β-catenin alleles, and thus we can determine the specific contribution of individual β-catenin transcriptional co-activators to the initiation and progression of non-melanoma skin cancers. Detailed analyses of SCC and BCC with impaired Wnt/-catenin signaling may reveal whether Wnt/-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/-catenin signaling together with other signaling pathways.
In the previous funding period, we used specific β-catenin mutant mouse strains we generated with a genetically defined SCC or BCC model. We have established two models for SCC (DMBA/TPA and UV-inducible K14-HPV8E6) and one RU486-inducible model for BCC (K5-CrePR x Ptch1fl/fl). We uncovered that targeting Wnt-secretion may represent a promising therapy of HPV-driven SCC. Recently, enhanced secretion of Wnt ligands was shown to be a driving force of other epithelial cancers, such as lung cancer and possibly also colon cancer. Colon cancer shares certain similarities with SCC: the epithelial origin, the involvement of Ras mutations and enhanced Wnt signaling. Unlike SCC however, the majority of colon cancer types develop towards metastasizing carcinoma connected to high patient mortality. In contrast to our knowledge concerning the role of the β-catenin pathway for the initiation of primary colon tumors, the understanding of Wnt signaling at the invasive stage is very limited. Especially the impact of enhanced Wnt-secretion to metastatic processes remains unclear. To determine the involvement of enhanced Wnt secretion and transcription-specific outputs of β-catenin in later stages of colon cancer we plan to establish a new model of sporadic metastasizing colon cancer. Such a model will be based on orthotopically transplanted intestinal organoids, combining unique inducible genetic alleles to block either Wnt-secretion or β-catenin-specific transcriptional outputs with various colon cancer-driving mutations introduced by CRISPR/Cas9. Precise analyses of this new model may reveal what type of Wnt-outputs should be targeted in later stages of colon cancer with respect to minimizing the side effects on normal intestinal homeostasis.