Donald R. Senger, PhD
Principal Associate in Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School
330 Brookline Avenue, RN 280E
Boston, MA 02215
Donald Senger received a Ph.D. in Biology from the University of Rochester in 1977 and subsequently pursued postdoctoral training at the Center for Cancer Research at the Massachusetts Institute of Technology. He joined the Pathology Department at Beth Israel Deaconess in 1980.
Our laboratory is focused on defining the cytoskeletal signaling pathways that control the morphogenetic mechanisms by which endothelial cells organize into new blood vessels. In particular, our work has suggested the hypothesis that defective angiogenesis, as it occurs in cancer and other pathologies, is largely due to defective cytoskeletal regulation that, in turn, results in defective vascular morphogenesis. Our translational goal is to identify therapeutic strategies for correcting key structural and functional defects associated with pathological neovessels. In particular, we are working towards drug-based strategies to rectify defects in tumor vasculature and thereby improve penetration of cytotoxic drugs and reduce tumor hypoxia (as required for effective radio-therapy).
We have identified several signaling pathways and associated effector molecules that are critical for capillary morphogenesis both in vivo and in vitro. These include integrin-mediated suppression of protein kinase A activity and marked increases in activities of the GTPase Rho and Src family kinases, all of which contribute to endothelial cell cytoskeletal regulation. In vivo, with a retrovirus-based mouse model of VEGF-driven angiogenesis, we have shown that Rho-mediated actin contractility serves a critical function in regulating capillary morphogenesis and that modest suppression of Rho-mediated contraction markedly impairs endothelial cell organization and angiogenesis. By contrast, increased RhoA activity promotes capillary morphogenesis and promotes functional neovascularization. With retroviral-based and pharmacological approaches in, we now are defining the specific functions of other signaling pathways and downstream effectors critical for capillary morphogenesis in tumors, with the goal of identifying additional molecular targets for rectifying defects in tumor vasculature and thereby improving delivery of chemotherapeutic drugs and effectiveness of radiation therapy.
New and Noteworthy Publications
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Senger DR. VEGF-A, cytoskeletal dynamics, and the pathological vascular phenotype. Exp Cell Res 2006 Mar 10; 312(5):538-48.
This review summarizes evidence supporting the concept that structural defects associated with pathological blood vessels are a consequence of defective vascular morphogenesis.
Senger DR. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 2005 Nov 25; 97(11):1093-107.
This review summarizes the functions of extracellular matrix molecules in regulating angiogenesis.
Senger DR. In vivo and in vitro models of Mammalian angiogenesis. Methods Mol Biol 2005; 294:269-85.
This "methods chapter" describes details of our retrovirus-based model for targeting specific signaling pathways during angiogenesis in vivo.
Senger DR. Matrix-specific activation of Src and Rho initiates capillary morphogenesis of endothelial cells. FASEB J 2004 Mar; 18(3):457-68.
This paper describes key signaling events through which interstitial collagen initiates reorganization of the endothelial cell cytoskeleton and inter-cellular junctions during the initial stages of capillary morphogenesis.
Hoang MV, Whelan MC,
Senger DR. Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc Natl Acad Sci U S A 2004 Feb 17; 101(7):1874-9.
This report defines importance of Rho-mediated actin contractility for organization of endothelial cells into neovessels and specifically identifies RhoA activity as a target for improving capillary morphogenesis.