# Iron, Ferroptosis and Ovarian Cancer

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $388,506

## Abstract

Summary
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 wil...

## Key facts

- **NIH application ID:** 10050681
- **Project number:** 2R01CA188025-06A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Suzy V Torti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,506
- **Award type:** 2
- **Project period:** 2014-09-16 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10050681

## Citation

> US National Institutes of Health, RePORTER application 10050681, Iron, Ferroptosis and Ovarian Cancer (2R01CA188025-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10050681. Licensed CC0.

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