PROJECT ABSTRACT
Ovarian cancer patients continue to have a high mortality rate due to late stage diagnoses and frequent relapse.
Ovarian cancer is not exclusively confined to the peritoneal cavity. Disseminated and circulating tumor cells are
often detected and are associated with worse survival outcomes. Therefore, focused efforts are needed to
identify factors that permit ovarian cancer cells to escape the peritoneum and identify sites that offer safe harbors
where the tumor cells can evade chemotherapy and be reactivated to cause relapse. Low numbers of
disseminated ovarian tumor cells have been detected in the bone marrow, however, mechanisms for bone
marrow homing and engraftment are not known. There is strong evidence that aberrant Rac1 GTPase signaling
contributes to tumor metastasis, invasion and survival, based on roles as a regulator of cell-cell adhesion, actin
reorganization and cell motility. Furthermore, Rac1 is crucial for engraftment and quiescence of hematopoietic
cells in the bone marrow niche. The Wandinger-Ness group previously reported that Rac1 is overexpressed and
the constitutively active Rac1b splice variant of Rac1, is elevated in high grade serous ovarian tumors.
Conversely, inhibition of Rac1 through perioperative use of a Rac1/Cdc42 dual inhibitor, was associated with
improved patient survival. Taken together, the data suggest that Rac1 GTPase may be an important driver in
ovarian cancer dissemination and enable engraftment in a protected niche such as the bone marrow from which
relapse may originate. The present proposal will test the hypothesis that Rac1 overexpression or hyperactivation
promotes ovarian cancer metastasis, and leads to tumor cell dissemination into the bone marrow and
establishment of a quiescent, cell population. Through a combination of in vitro cell based assays and xenograft
animal model studies, the impact of Rac1 overexpression and inhibition on invasion, metastasis and bone
marrow homing and quiescence will be tested. The experimental data will be used to parameterize a
computational model designed to simulate ovarian cancer cell homing to the bone and identify the most critical
nodes in the process that might serve as targets. Collectively, these studies will establish Rac1 as driver of
ovarian cancer cell dissemination and validate Rac1 as a high value therapeutic target with potential impact in
reducing ovarian cancer disease relapse.