Abstract LB013: Characterizing the role of exosomal miRNAs in metastasis

Abstract

Abstract Background: Exosomal microRNAs (Ex-miRs) play a pivotal role in intercellular communication, being transported via extracellular vesicles. In cancer, Ex-miRs influence tumor progression by regulating key cellular processes such as proliferation, angiogenesis, and metastasis. Their role in mediating communication between cancer cells and the tumor microenvironment highlights their significance as potential diagnostic and therapeutic targets. Methodology: In this study, we aimed to characterize the role of Ex-miRs in influencing the pre-metastatic niche (PMN) across 7 tumor types. We extracted high-confidence Ex-miRs (Log FC >= 2 in exosomes relative to expectation) and their targets (experimentally proven and targeted by at least 2 Ex-miRs) from various studies. Subsequently, we conducted gene ontology analysis to identify enriched pathways and selected the top 100 high-confidence Ex-miR targets based on the frequency of their appearance in the enriched pathways. These top 100 targets were consistently used throughout the analysis. Results: Pathway enriched among the top Ex-miR targets included common ones such as “wound healing” and “regulation of epithelial cell proliferation”, as well as cancer-specific, like “regulation of angiogenesis in kidney” (KIRC), “ossification” in lung (LUAD), and “positive regulation of cytokine production” in pancreatic cancer (PAAD). Similarly, 'Pathways in cancer' and 'MicroRNAs in cancer' ranked among the top 10 enriched KEGG pathways for all cancer types. Ex-miR targets exhibited cancer-specific downregulation of gene expression in TCGA-Normal Adjacent Tumors (NATs), taken as proxy for PMN, compared to healthy tissue samples in GTEx. We further examined the 3’UTR GC content of these targets and found that Ex-miR targets are GC-rich, consistent with the previous findings stating that Ex-miR bind to the 3’UTR region of the target gene, downregulating their expression. Fisher’s exact test revealed a significant overlap of cancer-specific tumor suppressor genes (TSG) with Ex-miR targets. Cox regression indicated that Ex-miR targets are associated with better survival in certain cancer types, such as BRCA, COAD and KIRC. Lastly, a Support Vector Machine (SVM) model using Ex-miR target gene expression classified responders and non-responders to neoadjuvant chemotherapy with a high AUROC compared to other gene signatures. Conclusion: Our study unveils the pivotal role of exosomal microRNAs in shaping the PMN in diverse cancers, underscoring the diagnostic and therapeutic potential of Ex-miRs. Citation Format: Piyush Agrawal, Gulden Olgun, Arashdeep Singh, Vishaka Gopalan, Sridhar Hannenhalli. Characterizing the role of exosomal miRNAs in metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB013.