Date of Completion

6-8-2016

Embargo Period

5-31-2019

Major Advisor

Suzy Torti

Associate Advisor

Christopher Heinen

Associate Advisor

Daniel Rosenberg

Associate Advisor

Pramod Srivastava

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Ovarian cancer is a highly lethal malignancy that has not seen a major therapeutic advance in over 30 years. We demonstrate that ovarian cancer exhibits a targetable alteration in iron metabolism. Ferroportin (FPN), an iron efflux pump, is decreased and transferrin receptor (TFRC), an iron importer, is increased in ovarian cancer tissue. Expression of FPN and TFRC are strongly associated with patient survival. Ovarian cancer tumor-initiating cells demonstrate a similar profile of iron excess. Iron deprivation induced by desferroxamine, knockout of IRP2, or overexpression of FPN preferentially blocks growth of tumor initiating cells. Iron restriction inhibits invasion, synthesis of MMPs and IL6, and reduces intraperitoneal spread of tumor cells in vivo. Growth of ovarian tumors is inhibited by induction of ferroptosis, an iron-dependent form of cell death. Thus, enhanced levels of iron create a metabolic vulnerability that can be exploited therapeutically. We show that this dependence is already evident in the tumor initiating cell and creates a new therapeutic opportunity. Thus, alterations in iron import and export in ovarian cancer result in an iron acquisitive phenotype and an increase in metabolically available iron. A reduction in intracellular iron decreases IL6, which reduces MMPs, invasion and intraperitoneal metastases. Iron dependence can be targeted in two ways: by reducing intracellular iron with chelators, or by treating with agents that induce iron-dependent cell death.

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