Disseminated intra-abdominal metastasis is the leading cause of death for women with epithelial ovarian carcinoma, indicating that intervention with the metastatic process may significantly improve long-term survival of ovarian cancer patients. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) of malignant cells from the primary tumor. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. The overall goal of this project is to define the interrelationships between events that contribute to dissemination of malignant cells, as a more detailed understanding of these processes will translate into novel diagnostic and therapeutic strategies. A unique feature of primary well-differentiated ovarian cancers is an increase in expression of the cell-cell adhesion molecule E-cadherin, with subsequent loss of ? E-cadherin expression and/or function during progression to metastasis. Our current findings indicate that ligand-, mutational-, or trans-activation of the epidermal growth factor receptor (EGFR) modulates key cellular events required for junction dissolution and subsequent cellular dissemination. Proposed experiments will test the hypothesis that microenvironmental factors influence metastatic dissemination by initiating cross-talk between activated EGFR and cadherins, thereby modulating E-cadherin expression and function, resulting in shedding of metastatic cells from the primary tumor. To address this hypothesis, Aim 1 will evaluate microenvironmental regulators of E-cadherin junctional integrity by examining the effect of EGFR activation on modulation of E-cadherin expression, function and trafficking. The impact of E-cadherin functional downregulation on acquisition of mesenchymal markers and proteinase expression will also be evaluated.
Aim 2 will characterize the kinetics of proteolytic release of the E-cadherin ectodomain (sE-cadherin) and evaluate the effects of sE-cadherin on cell-cell adhesion and cellular dispersion using organotypic dissemination models. Translational studies proposed in Aim 3 will evaluate the relationship between EGFR activation, proteinase expression, cadherin status and ectodomain shedding in ovarian tumor microarrays and investigate microenvironmental regulators in ascites. The proposed integrative analysis will fill significant gaps in knowledge and provide novel data regarding (a) E- and N-cadherin status of early and late stage tumors and metastases, (b) EGFR activation and EMT in ovarian tumor progression from well- to poorly- differentiated tumors, and (c) the presence of soluble microenvironmental regulators positioned for sustained interaction with tumor tissues. Relevance: The proposed studies utilize a novel integrative approach to address molecular mechanisms that potentiate ovarian cancer metastasis. A major clinical need remains for ovarian cancer-specific therapies that target metastatic disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA109545-01A2
Application #
7149896
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Jhappan, Chamelli
Project Start
2006-07-01
Project End
2006-12-31
Budget Start
2006-07-01
Budget End
2006-12-31
Support Year
1
Fiscal Year
2006
Total Cost
$279,937
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Leonard, Annemarie K; Loughran, Elizabeth A; Klymenko, Yuliya et al. (2018) Methods for the visualization and analysis of extracellular matrix protein structure and degradation. Methods Cell Biol 143:79-95
Klymenko, Yuliya; Johnson, Jeffrey; Bos, Brandi et al. (2017) Heterogeneous Cadherin Expression and Multicellular Aggregate Dynamics in Ovarian Cancer Dissemination. Neoplasia 19:549-563
Klymenko, Yuliya; Kim, Oleg; Stack, M Sharon (2017) Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer. Cancers (Basel) 9:
Loughran, Elizabeth A; Phan, Ryan C; Leonard, Annemarie K et al. (2017) Multiparity activates interferon pathways in peritoneal adipose tissue and decreases susceptibility to ovarian cancer metastasis in a murine allograft model. Cancer Lett 411:74-81
Bailey, Karen A; Klymenko, Yuliya; Feist, Peter E et al. (2017) Chemical Analysis of Morphological Changes in Lysophosphatidic Acid-Treated Ovarian Cancer Cells. Sci Rep 7:15295
Yang, Jing; Kasberg, William C; Celo, Angela et al. (2017) Post-translational modification of the membrane type 1 matrix metalloproteinase (MT1-MMP) cytoplasmic tail impacts ovarian cancer multicellular aggregate dynamics. J Biol Chem 292:13111-13121

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