Research in the Bielenberg laboratory focuses on studying the biology of cancer metastasis, the spread of malignant tumor cells from one site in the body to another, through blood vessels and lymphatic vessels. Pancreatic adeno-carcinoma is a devastating disease with only a 4% 5-year survival rate due to the lack of effective therapies. We propose a novel therapeutic approach to pancreatic carcinoma treatment that involves using neuronal guidance molecules called Semaphorins to inhibit neoplastic growth and progression. We have identified a common cell surface receptor that is expressed on pancreatic cancer cells, pancreatic carcinoma-associated endothelial cells (blood vessels), and lymphatic endothelial cells (lymphatic vessels) called Neuropilin 2 (NRP2). It is unusual to find a common target on several cell types within the tumor microenvironment. Therefore, NRP2 is an excellent target for therapy in pancreatic adenocarcinoma. We hypothesize that NRP2 is acting as a VEGF-reservoir in the cancer cells and as an enhancing co-receptor with VEGFR in the endothelial cells. We will test this hypothesis by examining the role of NRP2 in cancer cells as a reservoir for VEGF or as an autocrine mediator of VEGF signaling by overexpressing NRP2 in pancreatic carcinoma cells. In addition, we will test the necessity of NRP2 in tumor-associated angiogenesis and lymphangiogenesis in murine orthotopic pancreatic carcinoma models and in transgenic (K-ras+) pancreatic carcinoma models using NRP2-deficient mice. We predict that mice lacking NRP2 in the endothelial cells will have decreased tumor size, decreased proliferating capillaries (angiogenesis), decreased lymphatic vessel area, and decreased metastatic potential. Lastly, we hypothesize that Semaphorin 3F (SEMA3F), an inhibitory ligand of NRP2, will inhibit (lymph)-angiogenesis and metastasis in vivo. We propose preclinical trials in pancreatic carcinoma (both human and murine orthotopic models) to test SEMA3F purified proteins delivered as daily injections or in slow-release pumps. In addition, we will test SEMA3F retroviral infection to obliterate pancreatic cancer metastasis in the liver. Overall, our plans are to investigate a novel approach and a new target in pancreatic cancer.

Public Health Relevance

Our proposed studies will explore the biology of cancer metastasis and the molecular mechanisms involved in pancreatic adenocarcinoma. Our preclinical trials with Semaphorin 3F may have broader impact on many angiogenic and metastatic cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA155728-02
Application #
8318096
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2011-08-10
Project End
2014-01-31
Budget Start
2012-08-01
Budget End
2014-01-31
Support Year
2
Fiscal Year
2012
Total Cost
$227,070
Indirect Cost
$96,570
Name
Children's Hospital Boston
Department
Type
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Banyard, Jacqueline; Chung, Ivy; Migliozzi, Matthew et al. (2014) Identification of genes regulating migration and invasion using a new model of metastatic prostate cancer. BMC Cancer 14:387
Migliozzi, Matthew T; Mucka, Patrick; Bielenberg, Diane R (2014) Lymphangiogenesis and metastasis--a closer look at the neuropilin/semaphorin3 axis. Microvasc Res 96:68-76
Panigrahy, Dipak; Adini, Irit; Mamluk, Roni et al. (2014) Regulation of soluble neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration. Pathology 46:416-23
Shahrabi-Farahani, Shokoufeh; Wang, Lili; Zwaans, Bernadette M M et al. (2014) Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas. Lab Invest 94:752-65
Banyard, Jacqueline; Chung, Ivy; Wilson, Arianne M et al. (2013) Regulation of epithelial plasticity by miR-424 and miR-200 in a new prostate cancer metastasis model. Sci Rep 3:3151
Coughlin, Mark F; Bielenberg, Diane R; Lenormand, Guillaume et al. (2013) Cytoskeletal stiffness, friction, and fluidity of cancer cell lines with different metastatic potential. Clin Exp Metastasis 30:237-50