Viral GPCRs in brain cancer: from molecular signaling networks to new therapeutic targets?

Samenvatting

The role of viruses in the progression of the hallmarks of cancer has long been debated. My research group was the first to show that the human cytomegalovirus (HCMV)-encoded G protein-coupled receptor (GPCR) US28 is present in glioblastoma tumor samples, and that it activates inflammatory and angiogenic signaling pathways and induces tumor formation in vivo. Based on these findings I hypothesize that viral GPCRs can contribute to the hallmarks and development of cancer and accelerate tumor progression. Most studies so far have focused on US28. However HCMV encodes four GPCRs (US28, UL33, US27, UL78), suggesting that the molecular mechanisms underlying the contribution of these viral GPCRs to tumorigenesis are more complex than previously thought. The influence of cellular context (cell type, genetic background) also remains poorly understood.

To delineate the effects of viral GPCRs on inflammation, angiogenesis, metabolism and proliferative signaling, my research team will assess the activity of cellular signaling and metabolic networks in different brain (tumor) cell types. Data will be obtained using state-of-the-art in vitro (signaling and phenotypic assays (including dedicated siRNA/rescue approaches) and in vivo glioblastoma model systems (intracranial xenograft models; injection reporter-based viral GPCR-expressing or HCMV-infected cells), HCMV (mutant) strains (viral GPCR-knockout), transcriptomics and quantitative proteomics (metabolic profiling).. These experiments will provide global and mechanism-based datasets to construct in silico signaling models, will help in guiding future therapeutic strategies. Finally, llama-derived antibodies (nanobodies) against viral GPCRs will be generated to monitor and target viral GPCRs. This novel approach will be essential for the validation of viral GPCRs as therapeutic and diagnostic targets.

The overall aim of the proposed project is to elucidate the molecular mechanisms through which viral GPCRs reprogram cellular signaling and accelerate tumor progression, and explore their potential as therapeutic targets in glioblastoma, the most aggressive brain cancer in adults and children.

Kenmerken

Projectnummer

016.140.657

Hoofdaanvrager

Prof. dr. M.J. Smit

Verbonden aan

Vrije Universiteit Amsterdam, Faculteit der Exacte Wetenschappen, Afdeling Scheikunde & Farmaceutische Wetenschappen