The role of the guidance of extracellulare vesicles for the tumor support in the tumor microenvironment of B cell malignancies

• Applicant: Privatdozent Dr. Hinrich Hansen
• Subject Area: Hematology, Oncology
• Term: from 2011 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193281201

Cancer cells create a tumor microenvironment (TME) of proinflammatory cells, which supports the tumor growth and survival. The cell types influence each other through direct cell contact or released extracellular vesicles (EVs). EVs contain essential donor cell molecules to simulate a cell contact over distance. In vitro, a high concentration of Hodgkin lymphoma cell EVs was necessary to stimulate bystander cells to release tumor-supporting growth factors. In situ and semisolid 3D culture, tumor and bystander cells use long protrusions to guide vesicles over distance directly to the corresponding cell type. This leads to a functional accumulation of EV at the target cell. So far, it is not known what mechanisms guide high EV concentrations directly to the responder cells.In chronic lymphocytic leukemia (CLL), the malignant cells are found within the TME and in the peripheral blood. Outside the TME, they cannot survive for a long time, therefore they periodically migrate to the TME to receive survival signals. We will test the hypothesis that round-shaped suspended tumor cells form protrusions to supporter cells, when they enter the TME, and that they use this network of protrusions to optimize the vesicle-based communication between tumor and supporter cells. Because actin polymerization participates in protrusion formation and is stimulated by the tyrosine kinases LYN and SYK, we will study their influence on the extracellular vesicle-based communication in vitro and in the Eµ-TCL1 CLL mouse model. Tyrosine kinase inhibitors might suppress the tumor-supporting communication through vesicles and protrusion.

• DFG Programme: Research Grants