(PQ6) vGPCR-Mediated Paracrine Transformation for Kaposi Sarcoma

(PQ6) vGPCR 介导的卡波西肉瘤旁分泌转化

• 批准号: 10524182
• 负责人: Young-Kwon Hong
• 金额: $ 18.84万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524182
• 关键词: AIDS related cancer; Address; Affect; Animal Model; Animals; Artificial skin; Automobile Driving; Biogenesis; Blood Vessels; CD19 gene; Cancer Etiology; Cell fusion; Cells; Coculture Techniques; Colon Carcinoma; Data; Development; Endothelial Cells; Endothelium; Engineering; Event; Experimental Animal Model; Extravasation; Foundations; G-Protein-Coupled Receptors; Gene Expression; Goals; HIV; HIV Seropositivity; Human; Human Herpesvirus 8; Immune; Immunity; In Vitro; Individual; Inflammation; Injections; Kaposi Sarcoma; Keratin; Knockout Mice; Knowledge; Lymphocyte; Lytic; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Natural Killer Cells; Neoplasm Metastasis; Oncogenic; Organ; Parabiosis; Pathogenesis; Pathogenicity; Phenotype; Process; Proteins; Reporter; Role; Series; Serum; Skin; Solid; System; Therapeutic; Viral; Viral Genes; Viral Oncogene; Viral Proteins; Virion; Virus; Work; base; cadherin 5; cancer initiation; cell type; cofactor; design; exosome; extracellular vesicles; gain of function; humoral immunity deficiency; implantation; in vitro Model; innovation; insight; keratinocyte; malignant breast neoplasm; metaplastic cell transformation; microphysiology system; neoplastic cell; novel; paracrine; promoter; transdifferentiation; tumor; tumorigenesis; uptake; AIDS related cancer; Address; Affect; Animal Model; Animals; Artificial skin; Automobile Driving; Biogenesis; Blood Vessels; CD19 gene; Cancer Etiology; Cell fusion; Cells; Coculture Techniques; Colon Carcinoma; Data; Development; Endothelial Cells; Endothelium; Engineering; Event; Experimental Animal Model; Extravasation; Foundations; G-Protein-Coupled Receptors; Gene Expression; Goals; HIV; HIV Seropositivity; Human; Human Herpesvirus 8; Immune; Immunity; In Vitro; Individual; Inflammation; Injections; Kaposi Sarcoma; Keratin; Knockout Mice; Knowledge; Lymphocyte; Lytic; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Natural Killer Cells; Neoplasm Metastasis; Oncogenic; Organ; Parabiosis; Pathogenesis; Pathogenicity; Phenotype; Process; Proteins; Reporter; Role; Series; Serum; Skin; Solid; System; Therapeutic; Viral; Viral Genes; Viral Oncogene; Viral Proteins; Virion; Virus; Work; base; cadherin 5; cancer initiation; cell type; cofactor; design; exosome; extracellular vesicles; gain of function; humoral immunity deficiency; implantation; in vitro Model; innovation; insight; keratinocyte; malignant breast neoplasm; metaplastic cell transformation; microphysiology system; neoplastic cell; novel; paracrine; promoter; transdifferentiation; tumor; tumorigenesis; uptake

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.

项目摘要 建议该项目回答RFA-CA-19-032中的挑衅性问题6。 目的：旁分泌转化是一个理论概念，该概念是在几年前提出的 在Kaposi的肉瘤（KS）发展过程中观察到的非常规的“非自主”肿瘤发生， 最常见的艾滋病相关的恶性肿瘤。该建议旨在证明其存在，以剖析其 机制，确定其中的玩家，并使用我们的新动物来定义其在KS肿瘤发生中的作用 模型和设计的微生物生理平台。 理由：Kaposi的肉瘤疱疹病毒（KSHV）在皮肤和内部引起内皮细胞肿瘤，KS 器官。 KS肿瘤发生中的悖论是，虽然大多数KS肿瘤细胞都被视为最小的病毒感染 基因表达，只有裂解阶段细胞表达VGPCR，这是唯一必要的已知病毒癌基因 足以开发KS。 挑衅性问题：在注定死亡的细胞中表达的裂解病毒基因VGPCR如何引起癌症？ 挑战：由于缺乏适当的动物模型，该问题仍未得到答复 或研究发病机理，持久性和肿瘤发育的体内系统，这些系统概括了这种HIV/AIDS- 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血管化皮肤芯片 平台。使用这些技术进步，我们将证明旁分泌转化的存在，确定 其细胞（免疫细胞，艾滋病毒）和分子（VGPCR负载外泌体）玩家，并表征其 机理是KS肿瘤发生的主要致癌驱动力。 影响：我们的研究将通过定义数十年的KS肿瘤发育的难题 旁分泌转化的存在和机制。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受裂解感染的细胞之外，作为致癌驱动器，还将 扩展我们了解癌症的倡议，进展和转移的方式。此外，这项研究将 为新颖的反K疗法打开新的门，并提供可靠的理由来研究 其他非病毒肿瘤发生的同等非自主转化，例如乳腺癌和结肠癌。