We have found that Akt signaling contributes to some of the more notable abnormalities in tumor vascular stroma. Vascular abnormalities include the propensity for excessive vascular permeability leading to tissue edema and sluggish blood flow, extravasation of fibrin and other matrix proteins that alter the extracellular microenvironment, and the trafficking of inflammatory cells and tumor cells in and out of the tumor-associated vasculature. Our overall hypothesis is the same signaling pathways that govern chronic permeability also govern leukocyte extravasation and tumor cell extravasation. Thus in this application we are testing this hypothesis in the following 3 aims.
Aim 1 Test the hypothesis that inactivation GSK3 mediates Akt-driven baseline permeability and explores the signaling pathway from Akt to mTOR that contributes to angiogenesis and vascular permeability and the signaling that alters GSK3 phosphorylation in endothelial cell and tumor cells Aim 2: To explore the role of Akt and downstream signaling pathways on cellular trafficking of leukocytes and tumor cells across the endothelium.
Aim 3 : Test the hypothesis that Akt effects on chronic permeability, leukocyte adhesion and diapedesis and tumor cell metastasis are mediated through Akt inactivation of GSK3 and subsequent Snail repression of VE-cadherin. Disease Relevance:

Public Health Relevance

The overall goal of my laboratory is to study the integration of signaling pathways that control angiogenesis and microvascular function. No one project can study all pathways at once, but the current focus of the lab is on the Akt signaling pathway, how it is regulated and how it regulates microvascular formation and function. In addition to exploring molecular mechanisms, we also study clinically feasible approaches to target this pathway. This application is proposing to explore some of the downstream signaling pathways that mediate the effects of endothelial Akt signaling in pathological angiogenesis, including cancer. While Akt pathway inhibitors are under development, most of the cancer studies that utilize those inhibitors are focused on the inhibition of tumor cell signaling. We have found that the vascular response to rapamycin is an important part of that Akt pathway inhibitor's efficacy in preclinical models. Our hope for this project is that by carefully examining the mediators of Akt's function in pathological angiogenesis we can uncover novel stromal targets to expand the repertoire of cancer therapeutics. In addition, we hope to significantly aid in the progress towards an effective use of existing Akt pathway inhibitors in cancer by exploring the understudied stromal effects of this pathway. We anticipate our findings to be relevant not only to the management of tumor progression but to have particular applications in preventing metastasis

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA131152-04
Application #
8096756
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2008-07-01
Project End
2013-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
4
Fiscal Year
2011
Total Cost
$455,087
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
O'Donnell, Rebekah K; Falcon, Beverly; Hanson, Jeff et al. (2016) VEGF-A/VEGFR Inhibition Restores Hematopoietic Homeostasis in the Bone Marrow and Attenuates Tumor Growth. Cancer Res 76:517-24
O'Donnell, Rebekah K; Goldstein, Whitney E; Perruzzi, Carole et al. (2013) Overexpression of MyrAkt1 in endothelial cells leads to erythropoietin- and BMP4-independent splenic erythropoiesis in mice. PLoS One 8:e55095
Koduru, Suresh; Kumar, Lalit; Massaad, Michel J et al. (2010) Cdc42 interacting protein 4 (CIP4) is essential for integrin-dependent T-cell trafficking. Proc Natl Acad Sci U S A 107:16252-6