Project Details
Projekt
Elucidation of the pathophysiological contribution of CD44 expressed on myeloid and endothelial compartments to the development of chronic lymphocytic leukemia in vivo
Subject Area
Hematology, Oncology
Cell Biology
Cell Biology
Term
from 2020 to 2024
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 437764346
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of malignant B cells expressing CD19, CD5, and CD23 in blood, bone marrow (BM), and secondary lymphoid tissues. Tumor cell proliferation preferentially takes place in lymphoid organs and requires a specific microenvironment, which comprises various cell types, the extracellular matrix, and soluble factors. Immune cells such as T cells and myeloid cellular subsets and other accessory cells such as endothelial cells provide pro-survival and activation signals which can be mimicked in vitro by co-culture approaches. The supportive cellular crosstalk involves adhesion molecules such as integrins or CD44, which exert central functions due to their retention and activation features. CD44 is expressed on various immune and stromal cell types, and CD44 interactions with its major ligand, the extracellular matrix component hyaluronan, have been implicated in a variety of tumors. In CLL, elevated CD44 serum levels and CD44 variant (CD44v) isoform expression have been suggested as markers for disease progression. On the basis of our previous publication and preliminary results, we now propose that CD44 not only expressed on tumor cells but also in the microenvironment fulfils relevant functions in CLL pathophysiology. In particular, CLL cells have decreased survival benefits from co-cultures with macrophages isolated from Cd44fl/fl;Csf1rCre mice, i.e. lacking CD44. Similarly, co-cultures of CLL cells and CD44v6 or CD44 knockout endothelial cells deliver less viability advantage to CLL cells compared control endothelium-based co-cultures. The endothelial compartment is also relevant in light of the fact that CLL cells rely on continuous recirculation between blood and tissue to gather promoting signals. In this grant application, we aim to investigate the consequences of Cd44 loss on engraftment of murine leukemic cells. We will address whether CD44 expression on macrophages contributes to immunosuppression in CLL. We will also investigate the prosurvival and proliferative signals towards murine leukemia cells controlled by CD44 on macrophages cells. We will further dissect how the tumor cells modify the endothelial compartment and which role CD44 plays in the crosstalk of the tumor with the endothelium. These experiments will be performed in various Cd44 floxed mice crossed with Cre mice specific for the endothelium and the myeloid compartment. Analysis of patient samples will complement these studies and will place our findings in a clinical, prognostic and therapeutic context.
DFG Programme
Research Grants
