? E-cadherin is a calcium-dependent transmembrane molecule that mediates homophilic interactions that are critical in mediating cell adhesion. Disruption of E-cadherin function is a hallmark feature of esophageal cancer (a common cancer in the US and worldwide), and other epithelial cancers. This leads to the promotion of esophageal cancer cell migration and invasion. Our preliminary data reveal that overexpression of E-cadherin upregulates TGFb receptor II (TGFRII) and statistically significant coordinated loss of both in esophageal cancer tissues. We have used primary human esophageal epithelial cells to analyze the loss of E-cadherin by retrovirally introducing a dominant-negative mutant version of E-cadherin lacking the cytoplasmic tail resulting in augmented cell migration and invasion. Thus, our overall hypothesis is that there is functional interplay between E-cadherin and TGFRII in esophageal cancer cell migration, invasion and EMT. We will test our hypothesis by pursiung [sic] the following interrelated Specific Aims.
Specific Aim 1 : A. To identify the domain(s) mediating the physical interaction between E-cadherin and TGFRII. We will generate deletion mutants of TGFRII and E-cadherin and map the specific domains necessary for interaction in vitro and in vivo. B. To analyze the mechanistic effects on cell migration and invasion mediated by the TGFRII / E- cadherin interaction. We will use the above mentioned mutants and a dominant-negative mutant of TGFRII to test how the normal interaction and loss of interaction influences cell migration, invasion and EMT.
Specific Aim 2 : To determine how E-cadherin stabilizes TGFRII and regulates its degradation and function. We will analyze the effects of E-cadherin on TGFRII expression and determine the kinetics of TGFRII degradation by analyzing TGFRII association with the endosome or proteasome machinery.
Specific Aim 3 : To analyze the effects of loss of E-cadherin function in vivo using mouse models. We will use mouse models to investigate the loss of E-cadherin in the esophagus and how this pertains to the regulation of TGFRII function and the induction of tumorigenesis. In addition, new mouse models will be established using dominant-negative E-cadherin to directly model and recapitulate our in vitro findings. In aggregate, these studies will provide insights into the importance of E-cadherin and TGFRII to mediate esophageal cancer cell migration and invasion, hopefully translating into novel approaches for therapeutics. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK075379-01A1
Application #
7318546
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2007-08-10
Project End
2008-01-31
Budget Start
2007-08-10
Budget End
2008-01-31
Support Year
1
Fiscal Year
2007
Total Cost
$69,579
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Andl, Thomas; Le Bras, Grégoire F; Richards, Nicole F et al. (2014) Concerted loss of TGF?-mediated proliferation control and E-cadherin disrupts epithelial homeostasis and causes oral squamous cell carcinoma. Carcinogenesis 35:2602-10
Kadaba, Raghu; Birke, Hanna; Wang, Jun et al. (2013) Imbalance of desmoplastic stromal cell numbers drives aggressive cancer processes. J Pathol 230:107-17
Le Bras, Grégoire F; Taubenslag, Kenneth J; Andl, Claudia D (2012) The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression. Cell Adh Migr 6:365-73
Zaika, Elena; Wei, Jinxiong; Yin, Dengping et al. (2011) p73 protein regulates DNA damage repair. FASEB J 25:4406-14
Le Bras, Grégoire F; Allison, Gillian L; Richards, Nicole F et al. (2011) CD44 upregulation in E-cadherin-negative esophageal cancers results in cell invasion. PLoS One 6:e27063
Andl, Claudia D; McCowan, Kelsey M; Allison, Gillian L et al. (2010) Cathepsin B is the driving force of esophageal cell invasion in a fibroblast-dependent manner. Neoplasia 12:485-98
Andl, Claudia D (2010) The Misregulation of Cell Adhesion Components during Tumorigenesis: Overview and Commentary. J Oncol 2010:
Okawa, Takaomi; Michaylira, Carmen Z; Kalabis, Jiri et al. (2007) The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation. Genes Dev 21:2788-803
Takaoka, Munenori; Kim, Seok-Hyun; Okawa, Takaomi et al. (2007) IGFBP-3 regulates esophageal tumor growth through IGF-dependent and independent mechanisms. Cancer Biol Ther 6:534-40
Oyama, K; Okawa, T; Nakagawa, H et al. (2007) AKT induces senescence in primary esophageal epithelial cells but is permissive for differentiation as revealed in organotypic culture. Oncogene 26:2353-64

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