Matrix structure and microenvironment dynamics correlate with chemotherapy response in ovarian cancer

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Summary: Elevated extracellular matrix (ECM) associates with chemo-resistance and poor prognosis in cancer. Modifying the ECM could enhance response to chemotherapy. We measured chemotherapy-induced changes in the tumor microenvironment (TME) of two high-grade serous ovarian cancer (HGSOC) mouse models with different chemo-sensitivity. Carboplatin/paclitaxel treatment triggered dynamic transcriptional changes in immune and ECM-related pathways, and analyses of the ECM structure revealed modifications in the chemo-sensitive tumors. These changes, observed over twenty days post-chemotherapy, had relevance to HGSOC patient responses. Integrating transcriptomics with ECM structure metrics, we identified ECM targets, including lysyl oxidase (LOX), that might enhance effects of chemotherapy. Given alone or with chemotherapy, a pan-LOX inhibitor, PXS-5505, modulated fibroblast and immune cell distribution and decreased tumor stiffness in the less-responsive mouse model. Moreover, treatment with PXS-5505 before chemotherapy enhanced the therapeutic response. We conclude that pretreatment with ECM targeting agents may improve chemotherapy efficacy by altering ECM structure and immune responses.

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