Analysis and therapeutic blocking of Exosome-miRNA tumor-derived signaling in colorectal carcinoma (Short title: Exo-antimiR)

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Exosomes are small, nanoscale cellular membrane vesicles which can play important roles in cell-cell communication in various diseases. Tumor-derived exosomes can confer pro-tumorigenic effects, leading to tumor growth and survival, angiogenesis and metastasis. MicroRNAs (miRNAs) are small RNA molecules which specifically interact with target mRNAs, thus inhibiting gene expression. Many miRNAs show aberrantly high levels in cancer and thus contribute to the process of tumorigenesis and metastasis. Thus, miRNAs may well serve as targets for their therapeutic inhibition by anti-miRNA molecules, and for this purpose, anti-miRNA oligonucleotides (antimiRs) have been introduced. While different technologies are explored for the therapeutic in vivo delivery of antimiRs, several issues need to be addressed, including often low efficacies, non-specific delivery, toxicity or unwanted side effects. Notably, miRNAs can be transported by exosomes, and selectively taken up by other cells. This makes exosomes particularly interesting as delivery vehicles for small RNA molecules like antimiRs. Within this project, we now intend to establish for the first time a therapeutic antimiR-based miRNA inhibition through exosome delivery, and to explore the advantages of using exosomes from patients. To this end, we will focus on colorectal carcinoma (CRC). Exosomes can also serve as biomarkers, with the profiling of exosomal miRNAs representing a new diagnostic/prognostic tool. The advantage of this approach lies in the selective enrichment of these miRNAs within the exosome that may be particularly relevant in terms of cell-cell communication. This is a German-Russian collaboration project of the University of Leipzig with the Petrov Institute of Oncology, Russia (Dr. Anastasia Malek), aiming at (i) the detailed analysis of miRNA profiles in exosomes from CRC patients blood, and the correlation of the results with various CRC cancer subtypes, disease stages, chemotherapy response and other relevant clinical parameters (project part Russia), and (ii) the development of novel exosome-based antimiR delivery and miRNA inhibition strategies for selected miRNA candidates (Leipzig). The German project parts are subject of this application and cover the following aims: Aim 1: To establish innovative exosome-based antimiR delivery systems (Exo-antimiRs). Aim 2a: To assess the newly developed Exo-antimiR strategy for the inhibition of novel miRNA candidates identified from the Russian screening. Aim 2b: To employ exosomes from CRC patients for the generation of tailor-made Exo-antimiRs. Aim 3: To explore the anti-tumor and anti-metastatic potential of the newly developed patients exosome-based antimiR strategy (Exo-antimiRs) preclinically in vitro and in vivo.