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Viral GPCRs contribute to cancer progression via new modes of action

20 September 2023
Former PhD students, Maarten Bebelman and Irfan Setiawan, and Jeffrey van Senten, and PhD student Nick Bergkamp, from the Martine Smit/Marco Siderius lab (Chemistry & Pharmaceutical Sciences) have discovered that viral G protein-coupled receptors (GPCRs) may impact cancer progression through exosomal release and activation of the sphingolipid pathway.

 Two exciting studies recently published in iScience (DOI: 10.1016/j.isci.2023.107412) and Science signaling (doi/10.1126/scisignal.ade6737).

In the last decade it has become apparent that GPCRs encoded by herpesviruses (HCMV: human cytomegalovirus) may contribute to cancer progression. Maarten Bebelman et al, co-supervised by Michiel Pegtel (A-UMC, Cancer Center Amsterdam), reported that the viral GPCR US28 is secreted on exosomes from HCMV-infected cells and scavenging chemokines.  Since extracellular vesicles (EVs) are known to contribute to cancer progression, these studies might disclose novel pathways by which these viral GPCRs drive cancer progression and immune evasion.

Bergkamp and van Senten et al obtained mechanistic insight in the rewiring and re-localization of signaling networks by US28 in glioblastoma cells, a model for an incurable, therapy-resistant form of brain cancer. In close collaboration with Prof. Gunnar Klau (Algorithmic Bioinformatics, Department of Computer Science, Heinrich Heine University, Düsseldorf, Germany) the team showed that US28 expression was associated with increased signaling through the sphingosine-1-phosphate (S1P)/STAT3 pathway, a potent driver of gliomagenesis.

These studies provide novel insights and highlight fundamental molecular mechanisms involved in (viral) GPCR-associated exosomal release and signaling that may contribute to cancer progression.  

Picture (Nick/Maarten/Jeffrey): Nick Bergkamp, Maarten Bebelman and Jeffrey van Senten and team celebrating the iScience and Science signaling papers.