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

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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.