Kurzfassung

The normal hematopoietic stem cell (HSC) reversibly switches between dormancy and stress-induced proliferation. Our studies identified the endothelial protein C receptor (EPCR, Procr), a known marker for hematopoietic, neuronal, and epithelial stem cells, as a relevant functional regulator of HSC bone marrow retention as well as breast cancer stem cell tumorigenicity. Although the vascular roles of EPCR are primarily in anticoagulation and endothelial cell quiescence, EPCR-dependent HSC...
The normal hematopoietic stem cell (HSC) reversibly switches between dormancy and stress-induced proliferation. Our studies identified the endothelial protein C receptor (EPCR, Procr), a known marker for hematopoietic, neuronal, and epithelial stem cells, as a relevant functional regulator of HSC bone marrow retention as well as breast cancer stem cell tumorigenicity. Although the vascular roles of EPCR are primarily in anticoagulation and endothelial cell quiescence, EPCR-dependent HSC signaling suppresses activity of the small GTPase CDC42, increases integrin α4β1 (VLA4) affinity and counteracts mobilization signals that elevate HSC nitric oxide levels. Although EPCR is expressed by leukemic cell lines, it is unknown whether EPCR stem cell regulatory signaling influences leukemia development or resistance to therapy. Consequently, we want to test the role of EPCR in malignant hematopoiesis, where we hypothesize that EPCR will play a role in homing and retention in the bone marrow microenvironment (BMM). As the BMM protects LSC from eradication, we want to test if inhibition of EPCR may lead to a better response to standard chemotherapy. We will employ a novel mouse model of EPCR HSC signaling deficiency and provide mechanistic insights into specific effects of EPCR signaling on leukemic versus normal hematopoietic stem and progenitor transcriptome phenotypes. The function of EPCR in a multi-molecular signaling complex provides multiple opportunities for therapeutic modulation of EPCR function, while maintaining physiologically relevant homeostatic roles of this vascular receptor. As yet unknown roles of EPCR in leukemia development and LSC function, as demonstrated for HSC, promise to yield potential avenues for novel adjuvant leukemia therapy targeting LSC resistance.
Förderung Standort Mainz: € 35.000, Standort Frankfurt: € 35.000
 » weiterlesen» einklappen