Dissecting the role of tumor suppressing microRNAs in angiosarcoma

About This Grant

PROJECT SUMMARY/ABSTRACT Angiosarcomas are aggressive soft tissue sarcomas arising in endothelial cells with a poor prognosis and inadequate treatment options. Due to the rarity of the disease, there are limited resources for studying angiosarcoma and therefore little progress in identifying novel therapeutics. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have emerged as potential therapeutic targets in disease. MiRNAs undergo a series of enzymatic processing steps culminating with DICER1 cleavage to generate mature miRNAs. The miRNAs are then loaded into Argonaute (Ago) silencing complexes where the miRNA direct the complex to target mRNA transcripts for post-transcriptional repression. Global miRNA repression is a hallmark cancer. However, most cells require some expression of DICER1 and miRNAs for survival. Studies in mouse models of angiosarcoma have demonstrated that the endothelial biallelic deletion of Dicer1 and loss of miRNAs leads to angiosarcoma development. While most cells require DICER1 expression for survival, endothelial cells can not only survive, but this leads to transformation and tumorigenesis. This implicates the importance of miRNAs in repressing tumorigenesis in endothelial cells. However, it is unclear how miRNA loss leads to transformation or which tumor suppressing miRNAs contribute. This finding motivated a CRISPR- CAS9 loss of function screen with a miRNA focused gRNA library to identify critical tumor suppressing miRNAs. Results from this screen identified novel miRNA candidates that have not been interrogated in angiosarcoma. With this preliminary data, this proposal addresses the hypothesis that miRNAs are critical tumor suppressors in angiosarcoma and understanding their roles in tumorigenesis will lead to the identification of novel therapeutic interventions. In Aim 1, the functional consequences of the novel tumor suppressing miRNA candidates will be evaluated in normal cells and angiosarcoma. Aim 2 will test the repurposed FDA-approved antibiotic enoxacin for its potential to enhance miRNA processing as a therapeutic in angiosarcoma and as a tool to understand further understand miRNA functions. Completion of these studies will provide insights into the critical miRNA involved in repressing tumorigenesis, define their regulatory network, and determine the therapeutic relevance of enoxacin enhancement of miRNAs in angiosarcoma.