Related Experiment Video

Updated: Jun 13, 2025

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
04:01

Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics

Published on: March 15, 2024

892

NOTCH3 Drives Fatty Acid Oxidation and Ferroptosis Resistance in Aggressive Meningiomas

Nishanth S Sadagopan1, Mateo Gomez1, Shashwat Tripathi1

  • 1Northwestern University Feinberg School of Medicine.

Research Square
|June 12, 2025
PubMed
Abstract

Insights

NOTCH3 signaling drives aggressive meningiomas towards fatty acid oxidation, depleting lipids and conferring resistance to ferroptosis. This metabolic shift highlights potential vulnerabilities in NOTCH3-positive tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Research

Background:

  • NOTCH3 signaling is implicated in various cancers, including meningiomas.
  • Prior studies link NOTCH3 expression to higher-grade meningiomas and treatment resistance.
  • The metabolic phenotype associated with NOTCH3 activation in meningioma is largely unknown.

Purpose of the Study:

  • To investigate the metabolic consequences of NOTCH3 activation in meningioma.
  • To explore the role of NOTCH3 in regulating lipid metabolism and ferroptosis in meningioma cells.

Main Methods:

  • Single-cell RNA sequencing of NOTCH3-positive meningioma cell lines.
  • Overexpression of NOTCH3 intracellular domain (ICD) in a meningioma cell model.
  • Untargeted metabolomic, lipidomic, and bulk RNA sequencing analyses.
  • Functional metabolic and mitochondrial assays, including ferroptosis resistance studies.

Main Results:

  • NOTCH3 activation promotes a metabolic shift towards fatty acid oxidation (FAO).
  • This shift depletes lipid availability and enhances resistance to ferroptosis.
  • NOTCH3-high meningioma cells show increased CD36 expression and mitochondrial respiration.
  • NOTCH3 overexpression confers resistance to ferroptosis, which can be reversed by CPT1 inhibition.

Conclusions:

  • NOTCH3 signaling is linked to lipid metabolic reprogramming and ferroptosis evasion in aggressive meningioma.
  • This metabolic reprogramming may contribute to the malignant behavior of NOTCH3-positive meningiomas.
  • Targeting these metabolic vulnerabilities presents a potential therapeutic strategy for aggressive meningiomas.
Keywords:
Fatty Acid OxidationFerroptosisMeningioma MetabolismNOTCH3Tumor Microenvironment

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