Extracellular vesicle RNA as systemic modulators of the tumor microenvironment in B cell lymphoma

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Extracellular vesicles (EVs) are important mediators of intercellular communication and are involved in many physiological processes. They are present in almost any fluid compartment of our bodies and can be detected even at distant sites of their cell of origin. Within the last decade, their critical involvement in cancer development, progression and dissemination has become more and more obvious. EVs consist of a lipid bilayer membrane displaying cell surface proteins of their cell of origin and contain mainly protein and RNA molecules. It is now clear that EVs can interact with cells via their surface molecules and can transfer their content to target cells. The transferred material, e.g. proteins, messengerRNAs or microRNAs, was shown to be active in recipient cells, leading to changes in their phenotypes. Under physiological conditions, EVs act as mediators of immune responses, and there are indications that tumor-derived EVs contribute to disease-associated inflammation and immune suppression.Tumor cell-derived EVs have so far been mainly studied in solid cancers, and there is only little data on EVs produced by malignant cells in hematological diseases. Therefore, the aim of our proposed project is an extensive analysis of EVs, with a focus on exosomes, derived from malignant cells of chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and diffuse large B cell lymphoma (DLBCL). The study includes i) comparative proteome and RNA analyses of exosomes, with a focus on Y RNAs and microRNAs and their sorting mechanisms; ii) the identification of target cells within the hematopoietic microenvironment that take up tumor-derived exosomes in vitro and in mouse models; iii) a characterization of downstream changes within the transcriptome, secretome and signaling capacities of target cells, focusing hereby on inflammatory responses that are mediated by toll-like receptors; as well as iv) investigations to evaluate the impact of exosomes on B cell lymphoma development in suitable mouse models. Finally, we will v) investigate in a translational approach the potential of exosomes as biomarkers and as therapeutic target in preclinical studies in mice.