Patients with high-grade serous ovarian cancer (HGSOC) are frequently diagnosed with extensive metastatic disease, resulting in a poor prognosis. In HGSOC, metastasis occurs primarily by transcoelomic spread, where tumor cells detach from the primary tumor, float through the peritoneal fluid, and attach to the mesothelial layer to form new metastases. Tumor cells in patient ascites exist as single cells or in multi-cellular aggregates similar in size to experimental spheroids. We hypothesize that single cell and aggregate-based metastasis are distinct processes in HGSOC transcoelomic spread. To test this hypothesis, we will utilize a combination of engineering-based approaches (in vitro culture systems, multivariate modeling, computational fluid dynamics) and biological methods (molecular and cellular assays, analysis of patient samples, xenograft models). This proposal leverages a diverse, collaborative team that includes experts in engineering, biology, and the clinical presentation of HGSOC. Completion of the proposed studies will result in an improved understanding of mechanisms regulating transcoelomic spread and identification of potential targets for future work to control metastatic spread.
An improved understanding of different pathways used in metastasis will provide opportunities to slow the spread of high-grade serous ovarian cancer (HGSOC), improving patient prognosis and quality of life. In HGSOC, metastasis results from individual cells and aggregates of cells that break free from a tumor site, float through the peritoneum, and reattach in a new site. We hypothesize that single cell and aggregate- based metastasis are distinct processes and will test this hypothesis through analysis of patient samples, computational simulations of single cell and aggregate movement through the peritoneum, and experimental tests in vitro and in vivo.
