Pro-tumorigenic roles of a VHL isoform in Clear Cell Renal Cell Carcinoma

VHL 亚型在透明细胞肾细胞癌中的促肿瘤作用

基本信息

批准号：
10649049
负责人：
CRISLYN D'SOUZA-SCHOREY
金额：
$ 7.83万
依托单位：
UNIVERSITY OF NOTRE DAME
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-03-21 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649049
关键词：
Accounting Affect Behavior Binding Biochemical Biological Cell Line Cell Proliferation Cell Surface Proteins Cell model Cell surface Cells Chromosomal Instability Classification Clear cell renal cell carcinoma Communication Complex Conventional (Clear Cell) Renal Cell Carcinoma Data Development Diagnosis Disease Endothelial Cells Exhibits Exons Genes Germ-Line Mutation Human Hypoxia Inducible Factor Incidence Individual Investigation Knowledge Ligase Lipids Malignant Neoplasms Mediating Membrane Molecular Molecular Abnormality Mutation Neoplasm Metastasis Neoplasms Neoplasms in Vascular Tissue Nucleic Acids Paracrine Communication Pathologic Pathology Patients Phenotype Physiological Pilot Projects Play Population Pre-Clinical Model Protein Isoforms Proteins RNA Splicing Renal Cell Carcinoma Renal carcinoma Research Role Surface Testing Therapeutic Tissues Treatment Protocols Tumor Cell Line Tumor Promotion Tumor Suppressor Proteins United States VHL gene VHL protein Variant Vesicle Von Hippel-Lindau Syndrome Work Xenograft procedure autosome body system cancer cell cancer subtypes cancer type cell type extracellular vesicles gain of function innovation insight intercellular communication mouse model neoplastic cell novel therapeutics protein protein interaction response standard care targeted treatment translational potential tumor tumor microenvironment tumor progression tumorigenesis tumorigenic variant detection young adult

项目摘要

Pro-tumorigenic roles of a VHL isoform in Clear Cell Renal Cell Carcinoma. Kidney cancer or renal cell carcinoma (RCC), is presently the ninth most prevalent neoplasm in the United States. Its incidence has more than doubled in the developed world over the past couple decades and is projected to increase in burden worldwide. The most common subtype of RCC is clear cell RCC (ccRCC), accounting for nearly 80% of all cases. Of note, ccRCCs lack common genetic abnormalities observed in many other human cancers, thus impeding the use of more standard treatment regimens by targeted therapies. Greater than 90% of ccRCC tumors exhibit mutations in the VHL (von Hippel-Lindau) gene. The VHL tumor suppressor gene encodes three different protein isoforms: pVHL213, pVHL160 and pVHL172. pVHL172, an isoform lacking exon 2, is a naturally occurring VHL splice variant, that was recently characterized as lacking tumor suppressor function and having no effect on HIF expression or function unlike the other VHL isoforms, and effectively promoting tumorigenesis in xenograft ccRCC mouse models. Here, to better understand the cellular basis VHL172-driven ccRCC, we propose a set of self-contained studies to investigate paracrine signaling by VHL172 tumor cells. Based on robust preliminary data, we hypothesize that extracellular vesicles (EVs) derived from ccRCC tumors play a key role in the induction of pro-tumorigenic phenotypes. EVs harness select molecular entities—proteins, nucleic acids and lipids, and deliver these cargoes to recipient cells in the tumor microenvironment. We will test our hypothesis and subsequently leverage this work to investigate the role of EVs in preclinical models of ccRCC. These investigations will not only provide new information on EV-mediated intercellular communication in ccRCC, but also new therapeutic avenues to target patients diagnosed with this kidney cancer subtype.

VHL 亚型在透明细胞肾细胞癌中的促肿瘤作用。肾癌或肾细胞癌（RCC）是目前第九大最常见的癌症在美国，其发病率在发达国家增加了一倍多。过去几十年来，预计全世界的负担都会增加。 RCC 亚型是透明细胞 RCC (ccRCC)，占所有病例的近 80%。 ccRCC 缺乏在许多其他人类癌症中观察到的常见遗传异常，因此阻碍使用更标准的靶向治疗方案。的 ccRCC 肿瘤表现出 VHL (von Hippel-Lindau) 基因突变。抑制基因编码三种不同的蛋白质亚型：pVHL213、pVHL160 和 pVHL172。 pVHL172 是一种缺乏外显子 2 的同种型，是一种天然存在的 VHL 剪接变体，最近被发现缺乏抑癌功能且对 HIF 表达无影响，或与其他 VHL 亚型不同的功能，并有效促进异种移植中的肿瘤发生在这里，为了更好地了解 VHL172 驱动的 ccRCC 的细胞基础，我们提出了一系列独立的研究来研究 VHL172 肿瘤细胞的旁分泌信号传导。基于可靠的初步数据，我们捕获了源自 ccRCC 肿瘤在诱导促肿瘤 EVs 表型方面发挥着关键作用。选择分子实体——蛋白质、核酸和脂质，并将这些货物运送到我们将测试我们的假设并随后测试肿瘤微环境中的细胞受体。利用这项工作来研究 EV 在 ccRCC 临床前模型中的作用。研究不仅会提供有关 EV 介导的细胞间通讯的新信息在 ccRCC 中，还有针对诊断患有该肾病的患者的新治疗途径癌症亚型。