Receptor Cross-Talk in Metastatic Dissemination Epithelial ovarian carcinoma (EOC) will affect 1 out of every 69 women born in the US today. Currently, 80% of women newly diagnosed with EOC already have metastatic disease, indicating that intervention in the metastatic process will improve long-term survival of women with EOC. Metastasis occurs through a unique mechanism involving shedding of non-adherent cells as multi-cellular aggregates (MCAs) into the peritoneal cavity followed by intra-peritoneal (IP) implantation, and is often associated with peritoneal ascites. The factors that regulate the terminal transition from free-floating MCA to life-threatening peritoneally anchored metastatic lesion are currently unknown. Studies in the previous funding period highlighted the role of the soluble microenvironmental regulators EGF and lysophosphatidic acid (LPA) in regulation of epithelial (E)-cadherin (Ecad) expression and function. These mechanistic studies generated exciting new data on metalloproteinase-catalyzed Ecad ectodomain shedding, the role of the soluble Ecad ectodomain in human EOC ascites, and on changes in ?-catenin dynamics resulting from altered junctional integrity. Further, we performed a detailed IHC analysis of Ecad expression in primary human EOC, developed a panel of assays with which to evaluate MCA dynamics and metastatic success, and identified a set of gene products regulated by altering the mechanical environment of the cell. These results form the basis of the current hypothesis that cadherin switching and IP mechanobiology actively contribute to metastatic success. Studies in Aim 1 will focus on cadherin switching and MCA dynamics using a panel of cadherin-modified cell lines and a suite of in vitro assays designed to mechanistically evaluate the effect of cadherin composition on key cellular events in EOC metastasis. Experiments in Aim 2 will evaluate the effect of altered peritoneal mechanobiology on the suite of measures of MCA metastatic success and will determine whether IP mechanical forces affect mesothelial receptivity to metastatic implantation.
Aim 3 will combine analysis of human tumors and murine IP metastasis models for a direct examination of altered cadherin profiles, IP mechanobiology, and metastatic dissemination in vivo. The long-term goal of these studies is to cultivate a molecular level understanding of EOC metastasis, necessary for the development of EOC-specific therapies that effectively target metastatic disease.

Public Health Relevance

Epithelial ovarian cancer (EOC) will affect 1 out of every 69 women born in the US today. Currently 80% of women newly diagnosed with EOC already have metastatic disease. The long-term goal of these studies is to gain a molecular level understanding of EOC metastasis to design strategies to more effectively target metastatic disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109545-08
Application #
8680171
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Jhappan, Chamelli
Project Start
2004-07-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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Klymenko, Yuliya; Wates, Rebecca B; Weiss-Bilka, Holly et al. (2018) Modeling the effect of ascites-induced compression on ovarian cancer multicellular aggregates. Dis Model Mech 11:
Harper, Elizabeth I; Sheedy, Emma F; Stack, M Sharon (2018) With Great Age Comes Great Metastatic Ability: Ovarian Cancer and the Appeal of the Aging Peritoneal Microenvironment. Cancers (Basel) 10:
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
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
Klymenko, Y; Kim, O; Loughran, E et al. (2017) Cadherin composition and multicellular aggregate invasion in organotypic models of epithelial ovarian cancer intraperitoneal metastasis. Oncogene 36:5840-5851
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

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