# Lipid Metabolism Switch Triggers Invasive and Chemoresistant Epithelial Ovarian Cancer Phenotype

> **NIH NIH R01** · BROWN UNIVERSITY · 2024 · $334,546

## Abstract

PROJECT SUMMARY
Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer; frequently diagnosed after it has spread
from the ovary to the omentum fat pad. A major challenge to understanding and targeting EOC is the
heterogeneous nature of the disease, which makes it difficult to develop treatments that effectively target and
destroy all cancer cells. This heterogeneity results in complicated molecular landscapes with subpopulations of
highly invasive and chemoresistant tumor cells. It is critical to understand how this heterogeneity in cancer cells
develops and contributes to EOC disease progression. Polyploidal giant cancer cells represent a small
subpopulation of drug-resistant and dormant cancer cells that survive treatment and later awaken to form new
tumor cells through amitotic budding. Single cell biophysical analysis of tumor organoid cultures will be used to
determine how polyploidal giant cancer cells and other invasive cells contribute to EOC disease progression.
In the EOC tumor microenvironment, cancer cells frequently encounter metabolic stress from nutrient
deprivation, hypoxia, and toxic therapeutics, which can trigger metabolic reprogramming to promote cell survival.
Cells can undergo a metabolic shift from glycolysis to oxidative phosphorylation to meet energy demands of
survival and invasiveness; this shift in metabolism has been correlated with highly energetic mitochondria, lipid
droplet disappearance (lipolysis), and autophagy. This is especially important in PGCCs, which have increased
nutrient demands in part to their larger size and more invasive phenotype. Additionally, EOC metastases form
from multicellular aggregates that are shed from the primary tumor into the adipocyte-rich abdominal cavity.
Previous studies have demonstrated that peritoneal adipocytes can transfer free fatty acids to EOC cells to
provide cellular energy for metastatic tumor growth. Fatty acids provide a rich energy source for ATP-dependent
actin polymerization and actin-based protrusions are critical for cell migration and during metastasis.
We hypothesize that invasive EOC cells store energy from exogenous lipid sources (including adipocytes and
lipid-rich ascites fluid) in cytosolic lipid droplets, and under metabolic stress use these lipid droplets to generate
mitochondrial ATP that is required for invasive cell migration through autophagy. To prove this hypothesis, we
will use a novel 3D culture model and animal studies to track metabolic changes in individual chemoresistant
EOC cells as well as study heterogeneity in lipid droplet metabolism. The proposed research will investigate the
role of metabolic and treatment stress in activating lipid metabolism (Aim 1) and autophagy (Aim 2), and
determine how metabolic alterations in subpopulations of highly invasive cells (including PGCCs) contribute to
the development of aggressive tumors (Aim 3). The proposed studies will reveal novel mechanisms contributing
to cellular heterogeneity ...

## Key facts

- **NIH application ID:** 10893352
- **Project number:** 5R01CA266415-03
- **Recipient organization:** BROWN UNIVERSITY
- **Principal Investigator:** Michelle R Dawson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $334,546
- **Award type:** 5
- **Project period:** 2022-08-09 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10893352

## Citation

> US National Institutes of Health, RePORTER application 10893352, Lipid Metabolism Switch Triggers Invasive and Chemoresistant Epithelial Ovarian Cancer Phenotype (5R01CA266415-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10893352. Licensed CC0.

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