Abstract 779: Unraveling exosome-enabled cancer signaling: An integrated genomic approach

Abstract

Abstract Exosomes play important roles in mediating intercellular communication by transferring various cargos (lipids, RNAs and proteins) into recipients. Emerging evidence has indicated strong implication of exosomes and their RNA cargos in human and animal health including cancers, however, little is known about the mechanisms. In this study, we focus on a specific class of exosomal cargo, microRNAs, to explore new machineries underlying exosome-controlled microRNA secretion and trafficking and subsequently, to assess the regulatory impacts of cancerous noncoding RNAs to surrounding cells or remote tissues in terms of signaling transduction. Particularly, we developed a series of novel bioinformatics techniques that address important problems related to sequence motif finding (primarily based on short RNAs) and gene regulation network analysis (modeling complex structures that reflect multifaceted RNA cooperation and competition). Applying public exosomal microRNA sequence data and TCGA cancer transcriptomic profiles on various types of cancer, we have identified several candidate RNA motifs that might be responsible for guiding the transporter-mediated microRNA loading into exosomes, along with corresponding gene networks that are controlled by those circulating intruders. For example, in human colon cancer SW620 case, three 4-mer sequence motif patterns including [AU][CUG][UG]G, [CGU][UA][GU]G, [AUG][CG]U[UG] are highly enriched among exosomal microRNA sequences (with > 85% coverage, adj.p-value <=1.83E-07). Cell transfection experiments were performed on mutants of the constituent motifs versus their wild-type sequences, and have confirmed motifs, e.g., GGUG, were associated with microRNA loading into exosomes, mostly specific to a certain type of cancer. Results from network analysis further shows such exosomal microRNAs can regulate key signaling processes related to TGF-beta, MAPK, Neurotrophin, and Ras, in the recipient cells through interacting with significant numbers of target genes participating in those pathways. Moreover, the dynamic and conditional aspect of the network analysis enables the identification of microRNA regulatory modules as well as the characterization of regulatory transition across stages along cancer progression. Overall, we demonstrate here that exosome-mediated microRNAs regulation could be an effective channel for cancer cells to communicate with surroundings; and the packaging process is selective depending on unique sequence properties. More importantly, we present an integrative approach using computational modeling and genomic data mining to facilitate the discovery of disease-related exosome and microRNA functions, which can be generally useful for generating new insights and novel intervention tools. Citation Format: Juan Cui, Jiang Shu, Tian Gao, Haluk Dogan. Unraveling exosome-enabled cancer signaling: An integrated genomic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 779.