(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: 10674700
• 负责人: Young-Kwon Hong
• 金额: $ 57.76万
• 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/10674700
• 关键词: AIDS related cancer; Address; Affect; Animal Model; Animals; Artificial skin; Automobile Driving; Biogenesis; CD19 gene; Cancer Etiology; Cell Reprogramming; Cell fusion; Cells; Coculture Techniques; Colon Carcinoma; Data; Development; Endothelial Cells; Endothelium; Engineering; Event; Exclusion; 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; Rag1 Mouse; Reporter; Role; Series; Serum; Skin; Solid; System; Therapeutic; Vascularization; Viral; Viral Genes; Viral Oncogene; Viral Proteins; Virion; Virus; Work; 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 本项目旨在回应RFA-CA-19-032中的挑衅性问题6。 目的：旁分泌转换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常规的“非自主”肿瘤发生， 最常见的艾滋病相关恶性肿瘤。这个提案旨在证明它的存在，剖析它的 机制，确定其中的球员，并确定其在KS肿瘤发生中的作用，使用我们的新动物 模型和工程微生理平台。 基本原理：卡波西肉瘤疱疹病毒（KSHV）导致皮肤和内部的内皮细胞肿瘤，KS 机关KS肿瘤发生中的一个矛盾是，虽然大多数KS肿瘤细胞被最小的病毒感染， 基因表达，只有裂解期细胞表达vGPCR，这是唯一已知的病毒致癌基因，是必要的， 足以发展。 引发性问题：vGPCR，一种在注定死亡的细胞中表达的裂解性病毒基因，如何导致癌症？ 挑战：由于缺乏适当的体外工程动物模型，这个问题仍然没有答案 或离体系统，以研究发病机制，持久性和肿瘤发展，概括这种艾滋病毒/艾滋病- 相关恶性肿瘤。 创新与策略：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， 它的细胞（免疫细胞，HIV）和分子（vGPCR加载的外泌体）的球员，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肿瘤发展中的 旁分泌转化的存在和机制。这种挑衅性的旁分泌转化概念 这不仅会迫使我们把注意力从作为致癌驱动因素的裂解感染细胞转移到其他细胞， 扩展我们理解癌症的发生、发展和转移的方式。此外，本研究将 打开了一扇新的大门，新的抗KS疗法，并提供了一个坚实的理由，调查的存在， 在其他非病毒性肿瘤发生中，如乳腺癌和结肠癌，也存在类似的非自主转化。

项目成果

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

• DOI: 10.1161/circresaha.121.320565
• 发表时间: 2022-07-08
• 期刊: CIRCULATION RESEARCH
• 影响因子: 20.1
• 作者: Choi, Dongwon;Park, Eunkyung;Yu, Roy P.;Cooper, Michael N.;Cho, Il-Taeg;Choi, Joshua;Yu, James;Zhao, Luping;Yum, Ji-Eun Irene;Yu, Jin Suh;Nakashima, Brandon;Lee, Sunju;Seong, Young Jin;Jiao, Wan;Koh, Chester J.;Baluk, Peter;McDonald, Donald M.;Saraswathy, Sindhu;Lee, Jong Y.;Jeon, Noo Li;Zhang, Zhenqian;Huang, Alex S.;Zhou, Bin;Wong, Alex K.;Hong, Young-Kwon
• 通讯作者: Hong, Young-Kwon

The Lymphatic Cell Environment Promotes Kaposi Sarcoma Development by Prox1-Enhanced Productive Lytic Replication of Kaposi Sarcoma Herpes Virus.

• DOI: 10.1158/0008-5472.can-19-3105
• 发表时间: 2020-08-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Choi D;Park E;Kim KE;Jung E;Seong YJ;Zhao L;Madhavan S;Daghlian G;Lee HH;Daghlian PT;Daghlian S;Bui K;Koh CJ;Wong AK;Cho IT;Hong YK
• 通讯作者: Hong YK