Impact of aging on metastatic competence of the omentum

Metastasis to the omentum, an immune cell-rich fatty tissue that drapes from the stomach, causes substantial pain and bowel obstruction. It is difficult to completely resect the omentum and there are no effective strategies that minimize the risk of colonization of preserved omental tissues by occult cancer cells. Omental metastasis commonly occurs in women with ovarian cancer who are 60 years of age or older. Findings that ovarian cancer cells more effectively colonize the omentum of aged mice than young mice strongly implicate that aging increases metastatic competence of the omentum, but the underlying mechanisms are poorly understood. The goal of this study is to identify how aging increases metastatic competence of the omentum and develop strategies that decrease metastatic competence in older females. We recently discovered that a population of innate-like B cells expands in the uninvolved omentum of mice and women with early-stage ovarian cancer, and that these cells exert immunosuppressive properties and potentiate omental metastasis. Furthermore, we identified that innate-like B cells accumulate in the pre-metastatic omentum of young adult mice with ovarian tumors by homing from the peritoneal cavity. In new studies, we discovered that the normal omentum of aged females exhibits a striking expansion of innate-like B cells analogous to the pre-metastatic omentum of young adult females. We therefore hypothesize that heightened metastatic competence of the omentum in aged females stems from age-related increases in innate-like B cells, and that inhibiting homing of innate-like B cells to the omentum decreases metastatic competence in aged females. In this study, we will firstly determine whether heightened metastatic competence of the omentum in aged females stems from increases in innate- like B cells. Secondly, we will determine whether homing of innate-like B cells to the omentum is increased in aged females. Thirdly, we will delineate mechanisms that can suppress homing of innate-like B cells to the omentum in aged females and thereby decrease metastatic competence. These aims will be accomplished by a combination of approaches that utilize genetically modified mice, adoptive cell transfer, clinical specimens of human omentum, single cell analysis, and pharmacologic agents. If successful, our study will yield new mechanistic insights that explain why aging increases metastatic competence of the omentum and valuable insights into strategies for decreasing the risk of omental metastasis by occult ovarian cancer cells in older women.