TY  - JOUR
A1  - Sarma, Bhavishya
A1  - Willmes, Christoph
A1  - Angerer, Laura
A1  - Adam, Christian
A1  - Becker, Jürgen C.
A1  - Kervarrec, Thibault
A1  - Schrama, David
A1  - Houben, Roland
T1  - Artesunate affects T antigen expression and survival of virus-positive Merkel cell carcinoma
JF  - Cancers
N2  - Merkel cell carcinoma (MCC) is a rare and highly aggressive skin cancer with frequent viral etiology. Indeed, in about 80% of cases, there is an association with Merkel cell polyomavirus (MCPyV); the expression of viral T antigens is crucial for growth of virus-positive tumor cells. Since artesunate — a drug used to treat malaria — has been reported to possess additional anti-tumor as well as anti-viral activity, we sought to evaluate pre-clinically the effect of artesunate on MCC. We found that artesunate repressed growth and survival of MCPyV-positive MCC cells in vitro. This effect was accompanied by reduced large T antigen (LT) expression. Notably, however, it was even more efficient than shRNA-mediated downregulation of LT expression. Interestingly, in one MCC cell line (WaGa), T antigen knockdown rendered cells less sensitive to artesunate, while for two other MCC cell lines, we could not substantiate such a relation. Mechanistically, artesunate predominantly induces ferroptosis in MCPyV-positive MCC cells since known ferroptosis-inhibitors like DFO, BAF-A1, Fer-1 and β-mercaptoethanol reduced artesunate-induced death. Finally, application of artesunate in xenotransplanted mice demonstrated that growth of established MCC tumors can be significantly suppressed in vivo. In conclusion, our results revealed a highly anti-proliferative effect of the approved and generally well-tolerated anti-malaria compound artesunate on MCPyV-positive MCC cells, suggesting its potential usage for MCC therapy.
KW  - artesunate
KW  - Merkel cell carcinoma
KW  - MCC
KW  - polyomavirus
KW  - ferroptosis
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-203851
SN  - 2072-6694
VL  - 12
IS  - 4
ER  - 
TY  - THES
A1  - Kervarrec, Thibault
T1  - Histogenesis of Merkel cell carcinoma
T1  - Histogenese des Merkelzellkarzinoms
N2  - Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer. In approximately 80% of cases, genomic integration of the Merkel cell polyomavirus (MCPyV) is observed and overexpression of the two MCPyV T antigens (TAgs) is regarded as the main oncogenic determinant of MCPyV-positive MCC cases. However, the nature of the cells from which MCC arises is unknown. Therefore, the goal of the present work was to determine the cell of origin of MCC.
First, we characterized MCC patients’ tumors and demonstrated a high similarity of MCPyV- negative MCC with extracutaneous neuroendocrine carcinoma while MCPyV-positive MCC differs from these two groups with respect to morphology, immunohistochemical profile, genetics, origin and behavior. Based on the analysis of a trichoblastoma/MCC combined tumor, we demonstrated that a MCPyV-positive MCC can arise following MCPyV integration in an epithelial cell. In addition, the high similarity between trichoblastoma cells and Merkel cell (MC) progenitors of the hair follicle suggests that these hair follicle cells may represent a general start point for the development of MCPyV-positive MCC. A contribution of the viral TAgs to the development of the characteristic Merkel cell-like MCC phenotype is suggested by experiments demonstrating induction of Merkel cell markers upon TAg expression in human primary keratinocytes or hair follicle cells. As potential mechanisms mediating these phenotypic changes, we identified the capability of MCPyV LT to repress degradation of master regulator of MC development, i.e. the transcription factor ATOH1.
To conclude, our work suggests that MCPyV integration in epithelial cells of the hair follicle may represent an important path for MCC development.
N2  - Das Merkelzellkarzinom (MCC) ist ein seltener und aggressiver Hautkrebs. In etwa 80% der Fälle wird die genomische Integration des Merkelzell-Polyomavirus (MCPyV) beobachtet und die Überexpression der beiden MCPyV-T-Antigene (TAgs) gilt als die wichtigste onkogene Determinante der MCPyV-positiven MCC-Fälle. Die Ursprungszelle des MCC ist jedoch bisher unbekannt. Daher war das Ziel der vorliegenden Arbeit, die Hinweise auf die Herkunftszelle zu generieren. ...
KW  - Merkel-Zellkarzinom
KW  - Merkel cell carcinoma
KW  - Histogenesis
KW  - Hair follicle
KW  - Polyomavirus
KW  - Histogenese
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-199750
ER  -