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Epithelial ovarian cancer (EOC) has the 3rd highest mortality to incidence ratio of all cancers, and high-grade serous ovarian carcinoma (HGSOC) is the most common form of EOC. Even with resection and aggressive chemotherapy treatment, tumors recur in 70% of patients. Leukemia inhibitory factor (LIF) is an IL-6–type cytokine with known roles in cancer. The relevance of LIF in cancers is evident by clinical observations that high LIF-expressing tumors tend to have greater chemoresistance and a worse prognosis. HGSOC is one of the most hypoxic tumor types and hypoxia has been defined as a key driver of LIF overexpression in other cancer types. The effects of LIF and whether hypoxia is a driver within HGSOC have yet to be determined. Ovarian cancer cell lines cultured in a human plasma-derived 3D culture model (HuP3D) that recreates physiological oxygen levels of the normal ovary or HGSCOC tumors, primary HGSOC tumor analysis, and genomic data analysis have been used in our studies. In particular, a correlation between LIF and hypoxia was determined in primary HGSOC tissues and by genomic data. In vitro HuP3D models demonstrated that hypoxia-driven LIF overexpression has pro-proliferative effects and LIF neutralization was able to attenuate them. In addition, HuP3D HGSOC models revealed hypoxia-driven LIF overexpression induced drug resistance, and targeting LIF as an adjuvant treatment improved chemotherapy efficacy. Our preliminary results reveal the significance of hypoxia-driven LIF overexpression in HGSOC tumor progression and drug resistance, as well as confirm the feasibility and efficacy of the HuP3D model to study HGSOC. Identifying drivers of HGSOC tumorigenesis and chemoresistance is essential for development of adjuvant treatment targets capable of improving chemotherapy efficacy and preventing recurrence, thus improving patient survival.

First Advisor

Pilar de la Puente

Second Advisor

Maria Bell

Research Area

Biomedical Sciences