Elucidating spatiotemporal dynamics of nascent extracellular matrix in response to platinum treatment in ovarian cancer

PROJECT SUMMARY High-grade serous ovarian carcinoma (HGSC) is the most common type of ovarian cancer and has the 3rd highest mortality-to-incidence ratio of all cancers. Even with resection and aggressive platinum-based chemotherapy treatment, tumor recurrence occurs in 70% of patients, as a result of aberrant extracellular matrix (ECM) production leading to chemotherapy resistance. While the unidirectional effects of a dysregulated ECM composition and structure are well documented to contribute to cancer’s ability to resist treatment, knowledge on the effect of chemotherapy on spatial and temporal changes of the ECM remains limited. A main reason for this limitation is the lack of technologies that can track spatiotemporal dynamics of newly synthesized ECM in response to treatment in a biologically relevant yet controlled manner. In studies leading to this application, we have optimized platforms combining biomimetic tissue engineered cancer co-cultures and metabolic labeling allowing to track newly synthesized ECM dynamics in response to treatment and further implicate mechanotransduction signaling with the dysregulated ECM. Our translational approach includes well annotated and characterized HGSC cell lines and patient-derived xenograft (PDX) lines, as well as primary HGSC and PDX tumor biopsies. We will utilize innovative engineering approaches, metabolic labeling of newly synthesized proteins and state-of-the-art super resolution confocal imaging, proteomics from enriched newly synthesized proteins, machine-learning image analysis, flow cytometry, biomechanical characterization, and immunohistochemistry analysis to test our hypothesis. Specific aims are to identify platinum-induced spatiotemporal dynamics of newly synthesized ECM, determine how platinum-induced alterations in cell-ECM mechanotransduction relate to HGSC chemoresistance, and elucidate how ECM dynamics differ between platinum sensitive and platinum resistant HGSC tumors. Through these studies, we expect to have an important positive impact by opening new horizons for development of more efficacious ECM-targeted agents to mitigate HGSC chemoresistance, monitor treatment response, and ultimately improving chemotherapy effectiveness and mitigating chemoresistance.