Transforming growth factor-? (TGF-? has a dual role in tumorigenesis, initially functioning as a tumor suppressor and subsequently as a tumor promoter. A fundamental gap in knowledge exists in terms of mechanisms for the dichotomous function of TGF-?. The type III TGF-? receptor (T?RIII) has an emerging yet poorly understood role in regulating TGF-? signaling and carcinogenesis. We have establishing that T?RIII specifically inhibits cancer cell migration and invasion, in part by undergoing ectodomain shedding, releasing soluble T?RIII (sT?RIII). To investigate the mechanism of T?RIII function, the following hypothesis is proposed: Cell surface T?RIII decreases the migration of ovarian surface epithelial cells and ovarian cancer cells by activating Cdc42, disrupting the actin cytoskeleton, focal adhesion formation, polarity and inhibiting directional migration, while sT?RIII, generated through MMP-mediated ectodomain shedding, functions to inhibit TGF-? signaling and MMP production through a novel Smad1 pathway and T?RIII activates Cdc42 to inhibit the invasiveness of breast and ovarian cancer cells. This hypothesis will be addressed by four Specific Aims.
Specific Aim 1 : The mechanism by which T?RIII undergoes ectodomain shedding to produce sT?RIII will be established by examining the proteases involved, defining the site(s) of cleavage and how the process is regulated.
Specific Aim 2 : The mechanism by which T?RIII inhibits migration of ovarian surface epithelial cells and ovarian cancer cells will be established by examining the functional elements required for T?RIII function, and the effect of T?RIII-mediated activation of CDC42 pathways on polarity, directed migration, the actin cytoskeleton and focal complex formation.
Specific Aim 3 : The mechanism by which T?RIII inhibits invasion of breast and ovarian cancer cells will be established by examining the functional elements required for T?RIII function, the effect of sT?RIII on TGF-? cell surface binding, TGF-? signaling through Smad1 and MMP production and the effect of T?RIII-mediated activation of CDC42 pathways on invasion.
Specific Aim 4 : The effect of blocking T?RIII shedding and sT?RIII production, directly decreasing cell surface T?RIII and sT?RIII expression or expressing T?RIII and/or sT?RIII on both breast and ovarian cancer cell functions including proliferation, apoptosis, invasion and angiogenesis in vitro and tumor formation and metastasis in vivo will be explored to determine whether cell surface T?RIII and sT?RIII function in concert to decrease breast and ovarian cancer progression. These studies will define the mechanism by which T?RIII inhibits breast and ovarian cancer cell migration and invasion, including the role of ectodomain shedding, define the biological implications of ectodomain shedding of T?RIII in the context of human breast and ovarian cancers, and aid in the design of specific interventions for the prevention and treatment of human breast and ovarian cancers and other human cancers in which T?RIII has a defined role.

Public Health Relevance

We have demonstrated that a cell surface receptor for the transforming growth factor-? (TGF-?), the type III TGF-? receptor (T?RIII), is able to suppress cancer progression in a broad spectrum of human cancers, including cancers of the breast, lung, ovary, pancreas and prostate, by decreasing the ability of the cancer cells to migrate, invade and spread to distant sites. Regulating migration and invasion are also essential processes during embryonic development, tissue repair and in the immune response and have prominent roles in inflammatory and vascular diseases. Thus, these studies where we will investigate mechanisms by which T?RIII inhibits migration, invasion and metastatic spread are important to perform and relevant to public health as these mechanistic insights will define the biological functions of T?RIII in the context of human breast and ovarian cancers, increase understanding of the role of TGF-? signaling and of T?RIII in regulating migration and invasion and aid in targeting the TGF-? signaling pathway for the treatment of these cancers and other diseases in which migration and invasion or the TGF-? signaling pathway has a prominent role.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
3R01CA135006-05S1
Application #
8719538
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ogunbiyi, Peter
Project Start
2009-07-09
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$50,873
Indirect Cost
$18,470
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Knelson, Erik H; Gaviglio, Angela L; Nee, Jasmine C et al. (2014) Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth. J Clin Invest 124:3016-31
Osborne, Lukas D; Li, George Z; How, Tam et al. (2014) TGF-? regulates LARG and GEF-H1 during EMT to affect stiffening response to force and cell invasion. Mol Biol Cell 25:3528-40
Meyer, Alison E; Gatza, Catherine E; How, Tam et al. (2014) Role of TGF-? receptor III localization in polarity and breast cancer progression. Mol Biol Cell 25:2291-304
Knelson, Erik H; Nee, Jasmine C; Blobe, Gerard C (2014) Heparan sulfate signaling in cancer. Trends Biochem Sci 39:277-88
Hanks, Brent A; Holtzhausen, Alisha; Evans, Katherine S et al. (2013) Type III TGF-* receptor downregulation generates an immunotolerant tumor microenvironment. J Clin Invest 123:3925-40
Oh, Sun Young; Knelson, Erik H; Blobe, Gerard C et al. (2013) The typeýýIII TGF* receptor regulates filopodia formation via a Cdc42-mediated IRSp53-N-WASP interaction in epithelial cells. Biochem J 454:79-89
Mythreye, K; Knelson, E H; Gatza, C E et al. (2013) T?RIII/?-arrestin2 regulates integrin ?5?1 trafficking, function, and localization in epithelial cells. Oncogene 32:1416-27
Townsend, Todd A; Robinson, Jamille Y; How, Tam et al. (2012) Endocardial cell epithelial-mesenchymal transformation requires Type III TGFýý receptor interaction with GIPC. Cell Signal 24:247-56
Lambert, Kathleen E; Huang, Huang; Mythreye, Karthikeyan et al. (2011) The type III transforming growth factor-? receptor inhibits proliferation, migration, and adhesion in human myeloma cells. Mol Biol Cell 22:1463-72
Swaminathan, Vinay; Mythreye, Karthikeyan; O'Brien, E Tim et al. (2011) Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Cancer Res 71:5075-80

Showing the most recent 10 out of 13 publications