Background: Ovarian cancer affects approximately 25,000 women in the United States each year and remains one of the most lethal malignancies to affect women. This cancer is deadly because it often spreads, or metastasizes, from the ovary to distant sites before there are recognizable signs or symptoms. Once it has metastasized, it is very difficult to eliminate permanently, and women are often relegated to lifelong chemotherapy. Thus, the problem of metastasis, or how a cancer that started in one organ can move to and grow on another organ, is a fundamental challenge. The omentum, a fatty curtain of tissue that is suspended from the stomach and colon, is a preferential site of metastasis in ovarian cancer. My laboratory's research efforts focus entirely on the investigation of the biochemical and biological mechanisms that control metastasis.

What research has been accomplished by our laboratory to solve these problems? Cancer metastasis is a dynamic process that culminates in the formation of clinically detectable lesions at one or more discontinuous secondary sites. The processes of adhesion and invasion have been thoroughly studied, but the final steps in metastasis, called metastatic colonization, remain largely unknown. Functional studies using metastasis suppressor proteins are providing new insights into the molecular and cellular events that regulate metastatic colonization. My laboratory identified a novel role in ovarian cancer metastatic colonization for JNKK1/MKK4, a protein that helps cells respond to extracellular stress. JNKK1/MKK4 sets off a signaling cascade that ultimately results in suppression of cell growth. Clinical studies show that the amount of JNKK1/MKK4 is significantly decreased in ovarian cancer metastases as compared to the normal ovarian epithelial cells, consistent with its metastasis suppressor function. High levels of JNKK1/MKK4 are also correlated with improved patient outcomes after surgery. In highly metastatic human ovarian cancer cells, production of JNKK1/MKK4 reduces the number of metastases in mouse models by approximately 90% (P < 0.0001) and significantly prolongs animal survival (P = 0.0082). We recently have shown that JNKK1/MKK4 can inhibit the growth of ovarian cancer cells attached to the omentum, thereby reducing metastasis formation.

What is the research idea addressed in this proposal? The omentum is a primary site for ovarian cancer metastases. Basically, it is a fatty peritoneal fold that extends from the greater curvature of the stomach and covers most of the abdominal organs. Our data suggest that ovarian cancer cells associate with specific areas of the omentum that harbor clusters of immune cells. These structures, called "milky spots," are thought to enable immune cells to travel out of the omentum and into the peritoneal cavity and back. Despite the fact that the omentum is the main site for ovarian cancer metastases, relatively little is known about its cellular and structural composition, the structure and function of milky spots, and the preferential localization of various cancer cells to milky spots. Based upon published studies, data from my laboratory, and the experience of my research team, we suspect that ovarian cancer cells can exploit the normal physiological functions of milky spots in order to gain entry and progressively grow in the omental microenvironment.

What are the goals of this research project? We think that ovarian cancer cells specifically interact with structural components of the milky spots. The goal of this project is to learn more about the structure and function of milky spots in the mouse omentum, show whether injected ovarian cancer cells interact with these structures, and develop the tools needed to identify the specific cells and molecules that are involved in the interactions between ovarian cancer cells and the omental microenvironment.

What types of contributions will this study make to advance research? This study holds the potential to provide information about the interactions between ovarian cancer cells and cells within the omentum that are important for metastatic colonization. Moreover, it will provide information for other ovarian cancer researchers regarding the structure and function of the omentum. We also are developing a novel omentum organ culture model that we hope will be useful for a wide array of studies examining metastatic colonization, and potentially serve as a platform for therapeutic development and testing.

What types of patients will this research help and how? This research has the potential to help women with metastatic ovarian cancer by providing information on the interplay between ovarian cancer cells and their metastatic microenvironment. The findings from this research may change the strategies clinicians use to treat metastatic disease by influencing them to adopt a more aggressive use of cytoreductive surgery, or chemotherapy, to inhibit early interactions between ovarian cancer cells and key elements within the omentum. For example, future targeted therapies may be generated to target the metastatic microenvironment, making it less conducive to ovarian cancer cell growth.