Interplay Between KSHV and PDGFRA in AIDS-Kaposi's Sarcoma Oncogenesis

 描述(申请人提供)：卡波西S肉瘤(KS)，由KS疱疹病毒(KSHV)引起，是一种艾滋病相关恶性肿瘤(AIDS-KS)，是HIV感染者最重要的口腔恶性肿瘤。KS可以通过局部治疗、抗逆转录病毒治疗和化疗进行治疗；然而，据估计，超过一半的KS患者无法治愈。KS的特点是梭形细胞的增殖和KSHV基因引起的血管生成失调。针对AIDS-KS的基于发病机制的靶向治疗的有限成功，如使用mTORC1和PDGFR抑制剂，表明迫切需要增加我们对支持KS致癌的病毒和宿主因素的相互作用的了解，以开发靶向治疗；更重要的是，为当前的治疗提供信息。利用本实验室建立的Rac1依赖和KSHV依赖的KS致癌动物模型，我们从分子水平描绘了致癌的旁分泌轴，将KSHV癌基因vGCPR的表达与旁分泌因子的分泌联系起来，以确定新的治疗靶点。以公正的方式开展的新研究引导我们：1)确认PDGFR-α(PGFRA)是KS中激活的最强大的致癌驱动信号级联，指出PDGFRA是抗KS治疗的靶点；2)确定PDGFRA+间充质干细胞(MSC)是潜在的KS致癌前体细胞。我们推测，PDGFRA的显著激活及其在肿瘤中的驱动作用是KSHV针对这一途径的内在能力的结果，以增加PDGFRA+靶MSC的感染性、持久性和复制。(目的1)将研究PDGFRA在KSHV感染PDGFRA+MSC KS祖细胞和肿瘤发生中的作用：(目的2)鉴定有利于PDGFRA持续激活的宿主病毒相互作用。(AIM 3)将寻求使用遗传和药物抑制研究以及NGS(RNAseq)来识别和靶向PDGFRA介导的KSHV感染肿瘤发生的机制。这项工作将：1)确定KS前体细胞的表型特征，以及KSHV在这些细胞中的生物学如何导致肿瘤发生；2)确定关键的致病机制和新的治疗方法；3)了解PDGFRA和KSHV生物学在KS肿瘤中的相互作用及其如何影响发病机制和治疗反应

 DESCRIPTION (provided by applicant): Kaposi' s sarcoma (KS), caused by the KS herpesvirus (KSHV) is an AIDS-associated malignancy (AIDS-KS) and is the most important malignancy of the oral cavity in HIV infected individuals. KS can be treated with local therapy, anti-retroviral therapy and chemotherapy; however, it is estimated more than a half of KS patients will not be cured. KS is characterized by the proliferation of spindle cells and deregulated angiogenesis caused by KSHV genes. The limited success of targeted pathogenesis-based therapies in AIDS- KS such as the use of mTORC1 and PDGFR inhibitors indicate the urgent need to increase our understanding of the interplay of viral and host factors underpinning KS oncogenesis for development of targeted therapies; and more importantly, to inform current therapies. Using animal models of Rac1-dependent and of KSHV- dependent KS oncogenesis developed in our lab, we molecularly delineate an oncogenic paracrine axis connecting the expression of the KSHV oncogene vGCPR with secretion of the paracrine factors in order to define novel therapeutic targets. Novel studies carried out in an unbiased manner led us to: 1) Identify PDGFR- alpha (PGFRA) as the most potent oncogenic driver signaling cascade activated in KS pointing to PDGFRA as a target for anti-KS therapies 2) Identify PDGFRA+ mesenchymal stem cells (MSC) as potential KS oncogenic progenitors. We hypothesize that the prominent activation of PDGFRA and its driver role in the tumors is a consequence of the intrinsic ability of KSHV to target this pathway to increase infectivity, persistence and replication in PDGFRA+ target MSC. (AIM 1) Will study the role of PDGFRA in KSHV infection of PDGFRA+ MSC KS progenitors and oncogenesis: (AIM 2) Will Identify host viral interactions conducive to sustained activation of PDGFRA. (Aim 3) Will seek to use genetic and drug inhibition studies and NGS (RNASeq) to identify and targeting mechanisms of PDGFRA-mediated tumorigenesis in KSHV infected tumors. This work will: 1) Identify phenotypic characteristics of the KS progenitor and how the biology of KSHV in these cells leads to oncogenesis 2) Identify key pathogenic mechanisms and new therapeutic approaches 3) Understand the interplay between PDGFRA and KSHV biology in KS tumors and how it affects pathogenesis and response to therapy