The Notch pathway is a conserved signaling mechanism that functions to modulate cell- fate decisions. The overall objectives of this proposal are to define roles for Notch in cell- fate determination during lymphatic remodeling, and tumor lymphangiogenesis. Our general hypothesis is that Notch activity is necessary to assist in lymphatic remodeling. We hypothesize unique roles for different Notch family members in lymphatic growth and development, with a focus on Notch1, Notch3, and Notch4. We have discovered that VEGFR-3, a lymphatic regulator, is transciptionally regulated by Notch1 and Notch4. In contrast, a complex regulation of Prox-1 by Notch was uncovered with opposing roles for Notch1 and Notch4. Our general strategy will use a combination of in vitro lymphangiogenesis assays and mouse modeling to define the consequences of altering Notch activity in lymphatic endothelial cells. In addition, our preliminary studies implicate Notch as a regulator of tumor lymphatic growth and a factor controlling VEGFR-3 expression in tumor vessels and lymphatics.
In Aim I, we evaluate Notch function in isolated lymphatic endothelial cells with the goal of determining if Notch regulation of VEGFR-3 and Prox1 is key to lymphatic endothelial cell behavior.
In Aim II, we will analyze Notch mutant mice and activate Notch in dermal lymphatic endothelial cells to determine if Notch promotes lymphangiogenesis, lymphatic remodeling or lymphatic integrity.
In Aim III, we use a Notch inhibitor developed in the lab, a secreted antagonist of ligand-dependent Notch signaling, to evaluate if VEGF-C-mediated tumor lymphangiogenesis requires Notch. Our overall goal is to study both developmental and pathological lymphangiogenesis to better understand Notch function in lymphatics.

Public Health Relevance

Notch signaling is fundamental to proper vascular development. We present data strongly implicating Notch as a regulator of lymphatic development and pathologies. Thus, the studies outline in our proposal will aid us in understanding the functions of Notch in lymphatic differentiation and may be critical to developing strategies and therapeutics to correct lymphatic disorders or block tumor lymphangiogenesis.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-P (50))
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Mohla, Suresh
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Columbia University (N.Y.)
Obstetrics & Gynecology
Schools of Medicine
New York
United States
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Banerjee, Debarshi; Hernandez, Sonia L; Garcia, Alejandro et al. (2015) Notch suppresses angiogenesis and progression of hepatic metastases. Cancer Res 75:1592-602
Kangsamaksin, Thaned; Murtomaki, Aino; Kofler, Natalie M et al. (2015) NOTCH decoys that selectively block DLL/NOTCH or JAG/NOTCH disrupt angiogenesis by unique mechanisms to inhibit tumor growth. Cancer Discov 5:182-97
Shawber, Carrie J; Lin, Lu; Gnarra, Maria et al. (2015) Vascular Notch proteins and Notch signaling in the peri-implantation mouse uterus. Vasc Cell 7:9
Wu, June K; Kitajewski, Christopher; Reiley, Maia et al. (2015) Aberrant lymphatic endothelial progenitors in lymphatic malformation development. PLoS One 10:e0117352
Douglas, Nataki C; Zimmermann, Ralf C; Tan, Qian Kun et al. (2014) VEGFR-1 blockade disrupts peri-implantation decidual angiogenesis and macrophage recruitment. Vasc Cell 6:16
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Rhim, Andrew D; Oberstein, Paul E; Thomas, Dafydd H et al. (2014) Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 25:735-47
Murtomaki, Aino; Uh, Minji K; Kitajewski, Chris et al. (2014) Notch signaling functions in lymphatic valve formation. Development 141:2446-51
Murtomaki, Aino; Uh, Minji K; Choi, Yun K et al. (2013) Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium. Development 140:2365-76
Shah, Monjri M; Zerlin, Marielba; Li, Blake Y et al. (2013) The role of Notch and gamma-secretase inhibition in an ovarian cancer model. Anticancer Res 33:801-8

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