Skin tumor biology

Skin tumors are prevalent due to the high exposure of skin cells to mutation-inducing UV radiation. While melanoma is less common than other skin cancers, it poses a greater risk as it is more likely to metastasize, leading to higher mortality rates. Melanomas originate from melanocytes, the pigment-producing skin cells, and exhibit a remarkable number of genetic alterations characteristic of UV-induced tumors. One research focus of our group is to analyze the impact of various genetic mutations on the tumor, such as whether they are necessary for tumor development or proliferation, whether they may affect the efficacy of therapy, or whether they are bystander mutations without a decisive effect on the tumor cells. Furthermore, the accumulation of mutations within a signaling pathway suggests its significance for the tumor cells. Identifying relevant mutations and pathways is crucial not only for a deeper understanding of tumor development, but can also contribute to the development of new therapies or the optimization of existing ones.

Investigating factors that influence the proliferation and survival of cutaneous T cell lymphoma cells is another research focus of our group. This work is conducted in close collaboration with the cutaneous lymphomas research group led by Prof. Marion Wobser.

However, the principal focus of our research efforts for several years has been the study of Merkel cell carcinoma, a rare and particularly aggressive form of skin cancer. Merkel cell carcinoma gained broader attention in 2008 when it was discovered that a previously unknown virus from the polyomavirus group can be detected in the majority of Merkel cell carcinoma cases. This virus was subsequently named the Merkel cell polyomavirus (MCPyV). Our research has demonstrated that the tumor cells from Merkel cell carcinoma patients, in which the Merkel cell polyomavirus is integrated, rely on the expression of the viral oncogenic proteins known as the T-antigens. The interaction between the large T-antigen and the cellular retinoblastoma protein, which lifts the cell cycle blockade, is particularly crucial for the growth of these tumor cells. Additionally, we have found that phosphorylation of the large T-antigen at a specific site is necessary for its growth-promoting effect. Given the difficulty in directly inhibiting the viral proteins, we are currently focusing on identifying the cellular proteins required for the expression and phosphorylation of the T-antigen, with the aim of developing targeted therapies in the future.

The origin of Merkel cell carcinoma

Merkel cell carcinomas can be divided into two distinct subgroups based on their association with the Merkel cell polyomavirus (MCPyV). Merkel cell carcinomas linked to MCPyV have relatively few genetic mutations, while the virus-negative subgroup exhibits a high number of mutations characteristic of UV-induced skin tumors. The exact cellular origin of both MCPyV-positive and virus-negative Merkel cell carcinomas remains unclear. However, our analysis of combined tumors with Merkel cell carcinoma and epithelial components suggests that MCPyV-positive Merkel cell carcinomas may develop from trichoblastomas (a hair follicle tumor), while virus-negative Merkel cell carcinomas may originate from squamous cell carcinomas. This indicates that, contrary to previous assumptions, both subtypes could have an epithelial cell of origin. We plan to further investigate and validate this hypothesis using various experimental models.

Methods

The tumor biology research laboratory employs a range of experimental techniques, including organoid models and in-vitro cultures, to analyze the effects of genetically modified tumor cells or inhibitors. These methods encompass qRT-PCR, flow cytometry, immunoblotting, immunochemical staining, time-lapse microscopy, genetic manipulations (overexpression, knockdown or knock out via Crispr/cas9), and cell-based assays.