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Mesri Lab

Laboratory of Viral Oncogenesis

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Investigator / Contact Person Enrique Mesri

Research

A sixth of human cancers are caused by viruses. Dr. Mesri’s lab is the epicenter of an international translational research and training network to study human cancer-causing viruses. By understanding how infection with these viruses leads to cancer in vulnerable populations, His lab is developing new ways of preventing, diagnosing and curing viral malignancies. Their main focus is the Kaposi's sarcoma herpesvirus (KSHV), the causal agent of Kaposi's sarcoma (KS)—cancer that affects individuals with HIV/AIDS and the most frequent cancer of children and men in Africa. KS tumors are characterized by intense blood vessel proliferation (angiogenesis). The laboratory seeks to understand how KSHV infection is able to dysregulate host-signaling mechanisms to transform cells and activate angiogenesis, in order to identify viral and host therapeutic targets as a basis for the rational therapies to prevent and cure KS. Dr. Mesri’s Lab identified the viral G protein-coupled receptor (vGPCR), as a major KSHV oncogene, able to induce the secretion of VEGF and PDGF that cause malignant transformation and angiogenesis through autocrine and paracrine mechanisms. Using unique animal models of KSHV tumorigenesis developed by the lab showed that vGPCR is essential for KS tumor formation and a therapeutic target. Using these models the lab demonstrated that KSHV tumorigenesis is mediated by reactive oxygen species and that the FDA approved anti-oxidant NAC was able to not only to treat but also to prevent KSHV tumorigenesis; pointing to NAC as a potential chemoprevention and therapeutic drug that can be used to treat and prevent KS in endemic areas such as Africa. Using proteomics, Dr. Mesri found that the PDGF receptor (PDGFR) was the most activated oncogenic mechanism in KSHV tumorigenesis and also a therapeutic target found in all AIDS-KS tumors. Since they showed that KSHV activates PDGFR receptor through its ligands PDGFA and B that are induced by vGPCR, this discovery is paving the way for the use of Olaratumab, an anti-PDGF antibody, for immunotherapy of KS. They are currently using next-generation sequencing to study the mechanism of KSHV oncogenesis in mesenchymal stem cells where KSHV infection and PDGFR activation leads to the formation of tumorigenic cancer stem cells. Other discovery areas are the generation of immunocompetent mouse KS models to test KS immunotherapies, to study KSHV host cell reprogramming by epigenetic regulation, and to study how KSHV is able to manipulate the oxygen sensing machinery in order to maximize viral multiplication in tissues under normoxic and hypoxic conditions