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

VHL亚型在肾透明细胞癌中的促肿瘤作用 肾癌或肾细胞癌(RCC)目前是最常见的第九种癌症 美国的肿瘤。它在发达国家的发病率增加了一倍多。 在过去的几十年里，这一现象在全球范围内造成的负担预计将增加。最常见的 肾细胞癌亚型为透明细胞肾细胞癌(CcRCC)，占全部病例的近80%。值得注意的是， CcRCC没有在许多其他人类癌症中观察到的常见的基因异常，因此 通过靶向治疗来阻碍更标准的治疗方案的使用。超过90% 的ccRCC肿瘤表现出VHL(von Hippel-Lindau)基因突变。VHL肿瘤 抑制基因编码三种不同的蛋白质亚型：pVHL213、pVHL160和pVHL172。 PVHL172是一种缺失外显子2的异构体，是近年来发现的一种天然存在的VHL剪接变异体 缺乏肿瘤抑制功能并且对HIF的表达没有影响 与其他VHL亚型不同的功能，并有效促进异种移植瘤的形成 CcRCC小鼠模型。在这里，为了更好地理解VHL172驱动的ccRCC的细胞基础，我们 提出一套独立的研究来研究VHL172肿瘤细胞的旁分泌信号。 基于可靠的初步数据，我们假设细胞外小泡(EV)来源于 CcRCC肿瘤在促肿瘤表型的诱导中起着关键作用。电动汽车线束 选择分子实体-蛋白质、核酸和脂类，并将这些货物运送到 肿瘤微环境中的受体细胞。我们将检验我们的假设，并随后 利用这项工作来研究EVS在ccRCC临床前模型中的作用。这些 研究不仅将提供有关EV介导的细胞间通讯的新信息 在ccRCC中，也有新的治疗途径来针对被诊断为此肾脏的患者 癌症亚型。

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.