Donald R. Senger, PhD
Research Associate, Pathology, Beth Israel Deaconess Medical Center
Principal Associate, Pathology, Harvard Medical School
DF/HCC Program AffiliationAngiogenesis, Invasion and Metastasis
Our laboratory is focused on defining the signaling pathways and cytoskeletal-related mechanisms that control the organization of endothelial cells into new blood vessels within tumors, with the overall goal of identifying new therapeutic strategies for: (1) inhibiting tumor neovascularization and, conversely, (2) improving functional tumor neovascularization with the goal of improving penetration of cytotoxic drugs and improving oxygenation (as required for effective radio-therapy). We have identified several signaling pathways and associated effector molecules that are critical for capillary morphogenesis. 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 and capillary morphogenesis. In vivo, with a retrovirus-based mouse model of VEGF-driven angiogenesis, we have shown that RhoA serves a critical function in regulating capillary morphogenesis and that modest suppression of RhoA activity 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 vivo, we now are defining the specific functions of other signaling pathways and downstream effectors critical for capillary morphogenesis with the goal of identifying additional molecular targets for: (1) blocking tumor angiogenesis, and alternatively (2) rectifying defects in tumor vasculature and thereby improving drug delivery and oxygenation within tumors.
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