Ovarian cancer causes more deaths than any other gynecologic cancer in the US. The dismal prognosis of patients with advanced disease remains little changed in the past 30 years. New approaches are needed. In the last grant cycle, our laboratory discovered that ovarian tumor cells and ovarian cancer tumor-initiating cells (`cancer stem cells') acquire and retain substantially more iron than their non-malignant counterparts ? a phenomenon we named ?iron addiction?. This enhanced iron acquisition and retention facilitates growth of ovarian cancer. However, we found that this enhanced iron retention also makes ovarian cancer cells exquisitely susceptible to drugs that trigger ferroptosis, an iron-dependent form of cell death. Although iron is central to ferroptosis, little is known about how iron actually confers this susceptibility. In this application, we test the hypothesis that iron plays critical, novel, and previously undescribed roles in ferroptosis, and that new targets in the ferroptosis pathway that we recently discovered might lead to successful interventions in ovarian cancer. We approach this problem with two broad objectives: 1) to better understand the role of iron in ferroptosis; 2) to identify specific targets that will enhance the activity of ferroptosis inducers by fostering pro-ferroptotic pathways both in ovarian cancers themselves and in the ovarian cancer microenvironment.
Our Specific Aims are directed at these goals.
In Aim 1, we pursue pilot observations that ferroptosis inducers trigger a signaling network that fosters the generation of polyunsaturated lipid peroxides (the proximal `executioners' of ferroptosis). We propose that ferroptosis is propagated by both 1) transcriptional activation of iron-dependent pro-ferroptotic proteins that increase labile iron, and 2) engagement of a feed forward loop that disables the iron-dependent lipid desaturase SCD1 that we recently showed protects against ferroptosis. We will test our hypothesis using cell culture as well as murine models of ovarian cancer.
In Aim 2, we use state- of-the-art NanoSIMS imaging and MALDI-MSI to probe the sites of origin of the ferroptotic death signal, co- localizing iron with the oxidized lipids that typify ferroptosis. We confirm and expand these findings using organelle-targeted iron chelators.
In Aim 3, we assess how cells in the ovarian tumor microenvironment modify the response of ovarian cancers to drugs that induce ferroptosis. We focus on macrophages and fibroblasts, cells that are critically involved in ovarian cancer metastasis, which we discovered in pilot studies exert paracrine effects on lipid and iron metabolism that dramatically affect the degree of ferroptosis in ovarian cancer cells. Collectively, these experiments will enhance knowledge of ovarian cancer iron metabolism, explore regulatory pathways not previously linked to ferroptosis, and define the contribution of the tumor microenvironment to ferroptosis - efforts that will help to direct more effective use of ferroptosis inducers in ovarian cancer therapy.

Public Health Relevance

Ovarian cancer causes more deaths than any other gynecologic cancer, largely due to late stage at diagnosis and frequent treatment failures. In this proposal we expand on our initial findings that ovarian cancers are sensitive to ferroptosis, a novel iron-dependent form of cell death, by examining new enzymes and pathways that modify ferroptosis, finding where in the cell iron triggers the ferroptotic death signal, and examining how certain cells that surround the ovarian cancer affect the extent to which ovarian cancer can be killed by drugs that induce ferroptosis. These experiments may ultimately pave the way for more effective use of ferroptosis- inducing drugs in ovarian cancer therapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Connecticut
Schools of Medicine
United States
Zip Code
Blanchette-Farra, Nicole; Kita, Daniel; Konstorum, Anna et al. (2018) Contribution of three-dimensional architecture and tumor-associated fibroblasts to hepcidin regulation in breast cancer. Oncogene 37:4013-4032
Konstorum, Anna; Lynch, Miranda L; Torti, Suzy V et al. (2018) A Systems Biology Approach to Understanding the Pathophysiology of High-Grade Serous Ovarian Cancer: Focus on Iron and Fatty Acid Metabolism. OMICS 22:502-513
Chifman, Julia; Arat, Seda; Deng, Zhiyong et al. (2017) Activated Oncogenic Pathway Modifies Iron Network in Breast Epithelial Cells: A Dynamic Modeling Perspective. PLoS Comput Biol 13:e1005352
Basuli, D; Tesfay, L; Deng, Z et al. (2017) Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene 36:4089-4099
Deng, Zhiyong; Manz, David H; Torti, Suzy V et al. (2017) Iron-responsive element-binding protein 2 plays an essential role in regulating prostate cancer cell growth. Oncotarget 8:82231-82243
Lemler, David J; Lynch, Miranda L; Tesfay, Lia et al. (2017) DCYTB is a predictor of outcome in breast cancer that functions via iron-independent mechanisms. Breast Cancer Res 19:25
Paul, Bibbin T; Manz, David H; Torti, Frank M et al. (2017) Mitochondria and Iron: current questions. Expert Rev Hematol 10:65-79
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285
Torti, S V; Lemler, E; Mueller, B K et al. (2016) Effects of Anti-repulsive Guidance Molecule C (RGMc/Hemojuvelin) Antibody on Hepcidin and Iron in Mouse Liver and Tumor Xenografts. Clin Exp Pharmacol 6:
Yamamoto, Yusuke; Ning, Gang; Howitt, Brooke E et al. (2016) In vitro and in vivo correlates of physiological and neoplastic human Fallopian tube stem cells. J Pathol 238:519-530

Showing the most recent 10 out of 13 publications