Defining the mechanism of stromal mediated iron dysregulation in ovarian clear cell cancer

Ovarian clear cell cancer (OCCC) is one of the most highly treatment resistant subtypes of epithelial ovarian cancer. OCCC arises within endometriosis, the ectopic growth of endometrial stromal and epithelial cells, thus residing within a unique microenvironment characterized by high levels of iron due to repeated menstrual cycling. Iron is a double edged sword--critical for cell growth but extremely dangerous as labile iron (Fe2+) can participate in redox reactions producing toxic free radicals. Cells have stringent mechanisms to regulate the amount of intracellular Fe2+ known as the labile iron pool (LIP). Cancer cells, particularly OCCC cells, require high levels of this LIP referred to as ‘iron addiction.’ However, deficient understanding of how the iron rich endometriotic microenvironment impacts OCCC represents a critical knowledge gap preventing the development of effective targeted therapies. Our recent work identified a key role of endometriosis derived mesenchymal stromal/stem cells (enMSCs) in altering OCCC iron regulation. Loss of CD10, a transmembrane peptidase with intracellular signaling activity, in enMSCs promotes OCCC growth by exporting iron to feed adjacent cancer cells and rewiring cancer cell iron handling to maximize the LIP. The goal of this proposal is to identify the mechanism by which enMSCs dysregulate cancer cell iron homeostasis and determine the potential to therapeutically target this pathway in OCCC. We hypothesize that loss of CD10 mediates iron export through the PTEN/AKT pathway and that OCCC cells respond to CD10neg enMSCs by altering iron storage and uptake thus increasing their LIP. We further hypothesize that a novel labile iron-dependent drug delivery system will enable specific and potent OCCC therapeutic targeting. We propose the following: Aim 1: Define the mechanism by which CD10 loss enables enMSCs to export iron and support OCCC growth. Aim2: Delineate the mechanism of iron dysregulation in OCCC cells Aim3: Utilize labile iron-specific drug release to therapeutically target OCCC This work will define a new paradigm of stromal-mediated iron regulation within the tumor microenvironment and presents a novel and powerful therapeutic approach utilizing a selective and versatile drug delivery system to weaponize the unique ‘iron addiction’ in cancer cells. Justification for animal use: While the majority of the proposed work will utilize human models including patient derived cells and organoids, we also need to verify our findings and assess potential toxicity of the iron-specific therapeutic in a mouse model. Cell lines and human organoid models cannot determine the distribution and off target toxicity and overall efficacy of a new therapeutic compound. This requires a multi-organ, integrated physiologic system which includes an intact immune system to enable the eventual clinical development of this therapeutic.