(PQ6) vGPCR-Mediated Paracrine Transformation for Kaposi Sarcoma

项目总结 本项目是针对RFA-CA-19-032中的挑衅性问题6提出的。 目的：旁分泌转化是多年前提出的一个理论概念，用于解释 在卡波西肉瘤(KS)的发展过程中观察到非传统的“非自主”致癌作用，KS是 与艾滋病相关的最常见的恶性肿瘤。这一提议旨在证明它的存在，剖析它的 机制，确定其中的参与者，并使用我们的新动物确定其在KS肿瘤发生中的作用 模型和工程化的微生理平台。 理论基础：卡波西肉瘤疱疹病毒(KSHV)在皮肤和内部引起内皮细胞肿瘤KS 器官。KS致癌过程中的一个悖论是，尽管大多数KS肿瘤细胞潜伏着感染微量病毒 基因表达，只有裂解期细胞表达vGPCR，这是已知的唯一必需的和 足以满足KS开发的需要。 一个具有挑衅性的问题：在注定要死亡的细胞中表达的裂解病毒基因vGPCR是如何导致癌症的？ 挑战：由于缺乏合适的体外工程动物模型，这个问题仍然没有答案 或体外系统来研究艾滋病毒/艾滋病的发病机制、持久性和肿瘤发展- 相关的恶性肿瘤。 创新与策略：我们开发了一系列新型动物模型和带血管的皮肤芯片 站台。利用这些技术进步，我们将证明旁分泌变换的存在，确定 它的细胞(免疫细胞，HIV)和分子(vGPCR加载的外切体)玩家，并表征其 机制是KS肿瘤发生的主要致癌驱动因素。 影响：我们的研究将解决KS肿瘤发展长达数十年的难题，通过定义 旁分泌转化的存在及其机制。这一具有挑衅性的旁分泌转化概念 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 拓展我们对癌症发生、发展和转移的理解。此外，这项研究将 为新的抗KS疗法打开了一扇新的大门，并为调查KS的存在提供了坚实的理由 在其他非病毒致癌中，如乳腺癌和结肠癌中，等同的非自主转化。

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.