Summary
This research aims to determine the specific mechanisms by which platinum/taxane chemotherapy inadvertently stimulates tumor-associated membrane-anchored serine proteases (MASPs), promoting ovarian cancer metastasis, to develop effective blocking strategies.
What they want
Metastasis is a major cause of mortality in epithelial ovarian cancer (OC) patients, particularly high-grade serous ovarian cancer (HGSOC). Current treatments, including cytoreductive surgery and platinum/taxane chemotherapy (CPTX), often lead to recurrence and acquired resistance. This research investigates the paradoxical effect of clinically approved chemotherapy, which, while effective against primary tumors, can potentiate metastatic dissemination. The project focuses on the discovery that CPTX inadvertently activates tumor-cell associated membrane-anchored serine proteases (MASPs), which promote tumor dissemination and metastasis. The goal is to define specific mechanisms by which CPTX therapy stimulates MASP activities, enabling the establishment of favorable mesothelial niches and promoting metastases. The research plan involves two main objectives: 1) defining CPTX-induced molecular mechanisms that drive overactivation of MASPs, and 2) systematically defining cell-specific determinants and functional mechanisms of intraperitoneal metastasis caused by CPTX-induced activation of MASPs.
Deliverables
- Uncover important chemotherapy-induced metastatic mechanisms that can be exploited to develop more effective therapeutic strategies to specifically neutralize chemotherapy-driven pro-metastatic changes.
Technical requirements
- Use of patient-derived primary human ovarian tumor cells
- Use of patient ascites
- Use of genetically-defined ovarian tumor cell lines
- Use of preclinical organotypic mouse models
- Use of preclinical immunocompetent mouse models
