Involvement of leukemic-derived extracellular vesicles in tumor microenvironment metabolic rewiring

Chronic lymphocytic leukemia (CLL) represents the most frequent leukemia and is characterized by the accumulation of abnormal B-lymphocytes in the blood and lymphoid organs. Despite recent advances in therapies, CLL remains an incurable disease. During the last decade, the interactions between neoplastic cellsand the tumor microenvironment (TME), in particular immune cells and stromal cells, have been shown to be key in leukemogenesis and more particularly in CLL. Small extracellular vesicles (sEV) represent a very complex way of intercellular communication with implication in numerous physiological or pathological processes, notably in cancer. We have demonstrated that CLL-derived sEV can reprogram stromal cells and monocytes to promote CLL cell survival and immunosuppression. Our preliminary results indicate that sEV derived from the leukemic microenvironment (LME) are very important for the development of CLL in vivo in mice by targeting cells of the LME. Our data point to a mechanism involving the sEV in the metabolic rewiring of the LME, a crucial phenomenon for tumorigenesis and immunosuppression. The goal of this project is to study in depth with state-of-the-art metabolomics technologies, the metabolic content of sEV in CLL along with their intrinsic metabolic capabilities. In addition, we will analyze the impact of sEV on the metabolism of the different immune and stromal cells found in the LME, and on their functionalities. Elucidation of these complex mechanisms could enable to determine potential targets for new targeted therapies or innovating immunotherapies.