(PQ6) vGPCR-Mediated Paracrine Transformation for Kaposi Sarcoma

项目概要 该项目旨在回应 RFA-CA-19-032 中的挑衅性问题 6。 目的：旁分泌转化是多年前提出的一个理论概念，用于解释 卡波西肉瘤 (KS) 的发展过程中观察到非常规的“非自主”肿瘤发生，卡波西肉瘤是一种 最常见的与艾滋病相关的恶性肿瘤。该提案旨在证明其存在，剖析其 机制，识别其中的参与者，并使用我们的新动物来定义其在 KS 肿瘤发生中的作用 模型和工程微生理学平台。 理由：卡波西肉瘤疱疹病毒 (KSHV) 会在皮肤和内部引起内皮细胞肿瘤 KS 器官。 KS 肿瘤发生的一个悖论是，尽管大多数 KS 肿瘤细胞都潜伏着最少的病毒感染 基因表达，只有裂解阶段细胞表达 vGPCR，这是唯一已知的必需且重要的病毒癌基因。 足以用于KS开发。 挑衅性问题：vGPCR（一种在注定死亡的细胞中表达的裂解病毒基因）如何导致癌症？ 挑战：由于缺乏适当的体外工程动物模型，这个问题仍未得到解答 或离体系统来研究发病机制、持久性和肿瘤发展，概括了这种艾滋病毒/艾滋病- 相关恶性肿瘤。 创新与战略：我们开发了一系列新颖的动物模型和血管化皮肤芯片 平台。利用这些技术进步，我们将证明旁分泌转化的存在，识别 其细胞（免疫细胞、HIV）和分子（加载 vGPCR 的外泌体）参与者，并表征其 机制作为 KS 肿瘤发生的主要致癌驱动因素。 影响：我们的研究将通过定义 KS 肿瘤发展来解决长达数十年的难题 旁分泌转化的存在及其机制。这种旁分泌转化的挑衅性概念 不仅会迫使我们将注意力转移到作为致癌驱动因素的裂解感染细胞之外，而且 扩展我们理解癌症发生、进展和转移的方式。此外，本研究将 为新型抗 KS 疗法打开了一扇新的大门，并为研究 KS 的存在提供了坚实的理由 其他非病毒肿瘤发生中的等效非自主转化，例如乳腺癌和结肠癌。

PROJECT SUMMARY This project is proposed to respond to Provocative Question 6 in RFA-CA-19-032. Objective: Paracrine transformation is a theoretical concept that was proposed years ago to explain the unconventional “non-autonomous” oncogenesis observed during development of Kaposi’s sarcoma (KS), one of the most common AIDS-associated malignancies. This proposal is designed to prove its existence, to dissect its mechanism, identify the players therein, and to define its roles in KS tumorigenesis using our novel animal models and an engineered microphysiological platform. Rationale: Kaposi’s sarcoma herpes virus (KSHV) causes an endothelial cell tumor, KS, in the skin and internal organs. A paradox in KS oncogenesis is that while most KS tumor cells are latently infected with minimal viral gene expression, only lytic-stage cells express vGPCR, the only known viral oncogene that is necessary and sufficient for KS development. Provocative Question: How vGPCR, a lytic viral gene expressed in cells destined to die, can cause cancer? Challenges: This question remained unanswered due to the lack of proper animal models, engineered in vitro or ex vivo systems to study pathogenesis, persistence, and tumor development that recapitulate this HIV/AIDS- associated malignancies. Innovation & Strategy: We have developed a series of novel animal models and Vascularized Skin Chip platform. Using these technical advancements, we will prove the existence of paracrine transformation, identify its cellular (immune cells, HIV) and molecular (vGPCR-loaded exosome) players, and characterize its mechanism as the main oncogenic driver for KS tumorigenesis. Impact: Our study will address the decades-long conundrum on KS tumor development by defining the existence and mechanism of paracrine transformation. This provocative concept of paracrine transformation will not only force us to move our focus beyond the lytic-infected cells as the oncogenic drivers, but also expand the way we understand the initiation, progression, and metastasis of cancer. In addition, this study will open a new door to novel anti-KS therapeutics, and provide a solid justification to investigate the presence of equivalent non-autonomous transformation in other non-viral oncogenesis, such as breast and colon cancers.