# Defining cell intrinsic and extrinsic regulators of ferroptosis in pancreatic cancer

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $34,808

## Abstract

Project Summary
 Pancreatic cancer, most commonly diagnosed as pancreatic ductal adenocarcinoma (PDAC), is
amongst the top three leading causes of cancer death in the United States. These tumors are notoriously
resistant to apoptosis and richly populated by stromal and immune cells that create a therapy-resistant
microenvironment. Immunotherapy shows no benefit to patient survival, and despite advances in combinational
chemotherapy the 5-year survival rate sits around 11%. Therefore, investigating alternative forms of cell death
represents a unique strategy for targeting PDAC. Ferroptosis is a recently described form of cell death distinct
from apoptosis. It is dependent on an accumulation of lipid peroxides, generated by free labile iron, resulting in
osmotic cell lysis. Targeting ferroptosis can potently induce cell death in cultured PDAC cells. Yet, in PDAC
tumors in mice, triggering ferroptosis has a modest response with distinct cases of intrinsic and acquired
resistance currently limiting its therapeutic utility. It is therefore urgent that we address the gap between the in
vitro and in vivo responses for future clinical studies. In pursuit of this, I am taking a reductionist approach to
distill the mechanisms that regulate ferroptosis by osmotic and reductive-oxidative (redox) forces.
Mechanistically, it is known that ferroptosis requires osmotic pressure to induce cell lysis, but this fact is not
well studied within the current growing literature on ferroptosis in cancer. We hypothesize that cell death via
ferroptosis requires an imbalance of redox metabolism and sufficient osmotic pressure, to which PDAC cells
are particularly vulnerable. AIM I studies the biochemical dependencies between osmolarity and redox
metabolism. AIM II distinguishes changes in the external osmotic pressure from the cellular biochemical
adaptations, scaling up from monolayer to 3D culture techniques. Together, these aims investigate whether
ferroptotic cell death can be simplified to a balance of redox and osmotic pressure. The overall goals of this
study are to outline the boundary of these parameters and explore their application for targeting ferroptosis in
PDAC.

## Key facts

- **NIH application ID:** 10866348
- **Project number:** 5F31CA281241-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Heather Marie Giza
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $34,808
- **Award type:** 5
- **Project period:** 2023-05-02 → 2025-01-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866348

## Citation

> US National Institutes of Health, RePORTER application 10866348, Defining cell intrinsic and extrinsic regulators of ferroptosis in pancreatic cancer (5F31CA281241-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10866348. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*