Bowel obstruction is a leading cause of death in women with ovarian cancer and often stems from growth of tumors on the omentum, a fat pad that suspends from the stomach. The objective of this project is to determine the mechanisms that cause ovarian cancer cells to implant on the omentum, with the overarching goal of identifying more effective therapies for this lethal disease. Previous studies of ovarian cancer metastasis have mostly focused on investigating interactions of cancer cells with adipocytes, macrophages, fibroblasts and mesothelial cells. However, as these stromal cells are constituents of all visceral fat pads, interactions with these cells may not fully explain the tropism of ovarian cancer cells for the omentum. Neutrophils act as the first line of defense in response to infection or malignancy. Because the omentum is the major site of neutrophil influx into the peritoneal cavity, we speculate that neutrophils direct ovarian cancer cells to the omental niche. This study focuses on a phenomenon in which neutrophils extrude sticky DNA webs called neutrophil extracellular traps (NETs). NETs were originally discovered to trap microbes in infectious diseases but very little is known about the significance of NETs in cancer. Based on our preliminary studies, we hypothesize that ovarian cancer cells induce neutrophils to form NETs in the omentum, and that omental metastasis stems in part from entrapment of cancer cells by NETs in the omental niche. In this project, we will determine whether (1) ovarian cancers induce NET formation in the pre-metastatic omental niche, (2) omental metastasis of ovarian cancer depends on NET formation and (3) omental metastasis is decreased by treatment with agents that inhibit NETs.
These aims will be accomplished by evaluating patient clinical specimens, mouse tumor models and genetically modified mice that are defective in NET formation. Our study will provide new and provocative insights into the mechanisms that drive the propensity of ovarian cancer to colonize the omentum and the potential of repurposing NET-inhibiting agents for ovarian cancer therapy.
Bowel obstruction stemming from omental metastasis is a leading cause of death in ovarian cancer patients, but the mechanisms that cause ovarian cancer cells to implant on the omentum are poorly understood. By evaluating genetically modified mice, orthotopic tumor models and human clinical specimens, this project will investigate a novel mechanism by which neutrophils trap ovarian cancer cells in the omental niche. This project will provide new insights into the mechanisms that drive the propensity of ovarian cancer to colonize the omentum and more effective approaches to treat this lethal disease.
