Wednesday, April 2, 2025
4/2/2025
Chemotherapy induced MASP activation and ovarian cancer metastasis - SUMMARY Metastasis is the leading cause of high mortality in epithelial ovarian cancer (OC) patients. The most common and insidious OC subtype, high-grade serous ovarian cancer (HGSOC), is often diagnosed after it has already metastasized beyond the primary tumor site. Current clinical management for HGSOC is based on cytoreductive surgery and combination platinum/taxane chemotherapy (CPTX); however, effects are not durable, with as many as 80% of patients experiencing tumor recurrence and acquired resistance to chemotherapy. OC commonly metastasizes by shedding of tumor cells from the ovarian or fallopian tube surface epithelium directly into the peritoneal cavity where the tumor cells disseminate, attach to the mesothelial lining and invade surrounding organs. Clinically approved chemotherapies are designed to slow or stop tumor growth; however cancer cells can evolve between chemotherapy cycles, acquiring properties that allow them to survive and successfully disseminate, developing into life-threatening metastases. Different targeted molecular therapies are being developed as combination or maintenance therapies for OC that primarily target tumor growth, but have little effect on metastatic processes. Notably, several lines of compelling evidence point to the ability of clinically approved chemotherapy that is effective for treating primary tumors to potentiate metastatic dissemination of cancer cell subpopulations and paradoxically drive metastatic disease. We have discovered that chemotherapy used in first line treatments inadvertently activates tumor-cell associated membrane-anchored serine proteases, or MASPs, that promote tumor dissemination and metastasis. Our data emphasize the importance of determining whether anti-cancer agents aimed at cell division could inadvertently increase ovarian tumor persistence and tumor recurrence. The goal of this research is to determine specific mechanisms by which antimitotic CPTX therapy inadvertently stimulates tumor-associated MASP activities that enable establishment of favorable mesothelial niches and promote metastases so that effective blocking strategies can be developed. The research plan will use patient-derived primary human ovarian tumor cells, patient ascites, genetically-defined ovarian tumor cell lines, and preclinical organotypic and immunocompetent mouse models to 1) define CPTX-induced molecular mechanisms that drive overactivation of MASPs, and 2) systematically define cell-specific determinants and functional mechanisms of intraperitoneal metastasis caused by CPTX-induced activation of MASPs. At the completion of this study, we anticipate that we will uncover important chemotherapy-induced metastatic mechanisms that can be exploited to develop more effective therapeutic strategies to specifically neutralize chemotherapy-driven pro-metastatic changes.
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