Interplay between PDGFRA, oxygen-regulated translation and KSHV in Kaposi's sarcomagenesis

点击翻译按钮获取中文摘要

In spite of continuous improvements in our understanding of KSHV KS sarcomagenesis and the implementation of rationally designed therapies based on these advances, advanced AIDS-KS is mostly an incurable disease and many of the most promising new therapies continue to have major roadblocks and implementation problems particularly in the setting of ART. Our lab has made major contributions to the elucidation of viral mechanisms of oncogenesis and the host oncogenic mechanisms they elicit and the implementation of potential therapeutic approaches. In the last cycle of this R01:1) We have shown that KSHV lytic genes; and particularly the vGPCR oncogene can induce PDGF-mediated activation of PDGFRA, that PDGFRA is the most prominently activated RTK in AIDS-KS that is an oncogenic driver and a therapeutic target in AIDS-KS which in the Imatinib trials showed clinical prowess. 2) Based on the insight that PDGFRA is a critical oncogenic pathway recruited by the KSHV we reasoned that an oncogenic KS progenitor should be a PDGFRA(+) cell. This led us to the identification of PDGFRA mesenchymal stem cells as KS progenitors and PDGFRA; not only as a phenotypic marker, but also as an enabler of KSHV oncogenesis in an angiogenic KS- like environment. This discovery led to the development of a new KSHV infection-to-tumorigenesis system that allows to dissect the effect of the angiogenic microenvironment and the contribution of viral and host mechanisms to oncogenesis, using in vitro and in vivo models 3) We found that KSHV ability to regulate the oxygen sensing machinery allows the virus to coopt the hypoxia-regulated alternative translation initiation machinery eIF4EH activated by HIF2a and mediated by eIF4E2 cap-binding protein, which we found was essential for KSHV replication, for escaping the viral shut-off and for PDGFRA driven pathogenesis in MSCs. The importance of this discovery is that through its regulation of the oxygen sensing machinery (O2SM) the virus can access to translation initiation plasticity (TRIP), defined as the ability for KSHV to alternatively initiate protein synthesis using both the initiation complex eIF4E bearing a cap-binding regulated by the PI3K-AKT- mTORC1-HIF1a axis (eIF4E1 cap-binding) or the eIF4EH (eIF4E2 cap-binding) regulated by HIF2a. We hypothesize that this confers to KSHV several adaptive advantages that we will study in: Aim 1) It allows the virus to maximize replication in different oxygen levels corresponding to variety of tissues and pathophysiological conditions and It may allow the virus to bypass stress and innate immunity-related kinases (PERK and PKR) targeted eIF2a inhibition 2) It may be employed by viral oncogenes such as vGPCR and/or its host cell signaling mediators such as PDGFRA for proliferation and the induction of direct and paracrine oncogenesis Aim 3) Could allow the transformed host cell to be plastic and adaptive in the context of AIDS-KS therapies targeting PDGFRA such as Imatinib, which are known to target the PDGFRA-AKT-mTOR-E1-HIF1a pathway.