Human polyomaviruses (HPyVs) are small dsDNA viruses that infect most people. So far, 12 human polyomaviruses have been identified and antibodies against each of them can be detected in >50% of the subjects examined. HPyVs seem to establish a harmless life-long infection in healthy subjects. However, in immunocompromised patients, HPyVs can reactivate and may cause kidney defects, progressive multifocal leukoencephalopathy or trichodysplasia spinulosa. One HPyV, Merkel cell polyomavirus, is associated with Merkel cell carcinoma, a rare, but aggressive skin cancer. Little is known about the natural host cells of these viruses. We study the transcriptional activity of these viruses in different cell types and investigate signalling pathways that may lead to reactivation.
Neuroblastoma (NB) an embryonal cancer of the nervous system is the most common extracranial tumor in children, often with metastatic spread and therapy resistance. This calls for new translational research strategies identifying novel therapeutic targets in childhood tumors including the use of cell culture and experimental animal models to develop better therapy for children with NB. In our research plan, we focus on investigating the implication of inflammatory mediators in NB tumourigenesis, growth and survival. In particular, we focus on the role of the eicosanoid pathway in NB with emphasis on signal transduction mechanisms downstream of eicosanoid receptors. In addition, we investigate the role of inflammatory cells that infiltrate NB in the context of how they are affected by intervention of the eicosanoid synthesis pathway and how the eicosanoid pathway and pro-inflammatory cytokines may co-operate in the promotion of tumor development, immune suppression and chemoresistence. Current and newer agents that specifically target components of inflammatory cascades could change the approach to treat childhood tumors, especially as an adjuvant therapy because their benefits may lie in the synergism with conventional cytotoxic treatment, irradiation and /or other novel agents targeted against other procarcinogenic pathways. Human NB cell lines of different clinicobiological subsets and transgenic mouse model (MYCN) giving rise to metastatic murine NB will be used to investigate the potential of specific therapy using different inhibitors of eicosanoid pathways and other closely related and converging inflammatory cascades.
Signal transduction pathways
Research in our group focuses on the mitogen-activated protein kinase (MAPK) pathway and the cAMP/cAMP-dependent protein kinase (cAMP/PKA) pathway. Both pathways paly import roles in cellular processes such as proliferation, differentiation, cell survival, cell death, migration, and gene regulation. Extensive interaction (cross-talk) exists between the MAPK and PKA pathways. We are especially interested in MK5/PRAK, a protein kinase that belongs to the MAPK pathway. MK5/PRAK has been shown to possess tumorigenic, as well as tumour suppressive properties in cell culture and in animal models. We elaborate on the molecular mechanisms of this protein in tumorigenesis and try to identify novel specific inhibitors against MK5/PRAK which can be used in cancer therapy.