NOTCH3 Enhances Fatty Acid Oxidation and Ferroptosis Resistance in Aggressive Meningiomas

Overview

This study reveals that NOTCH3 activation in meningioma cells promotes fatty acid oxidation (FAO) by depleting fatty acid pools, thereby conferring resistance to ferroptosis. These metabolic adaptations may contribute to tumor aggressiveness and therapeutic resistance in NOTCH3-expressing meningiomas.

Background

The NOTCH signaling pathway, particularly the NOTCH3 receptor, plays a critical role in cell fate and tissue homeostasis, with restricted expression in vascular smooth muscle and the central nervous system. NOTCH3 has been implicated in various cancers and vascular diseases, and recent evidence identifies it as a driver of tumor growth and radiation resistance in meningiomas. However, the metabolic consequences of NOTCH3 activation in meningiomas have not been well characterized. Understanding these metabolic changes is crucial as tumor metabolism influences cancer cell survival and treatment response.

Data Highlights

Metabolomic and lipidomic profiling of meningioma cell lines overexpressing NOTCH3 intracellular domain (ICD) demonstrated depletion of fatty acids utilized for fatty acid oxidation (FAO). This metabolic shift was associated with protection from ferroptosis, a form of iron-dependent cell death. NOTCH3 overexpression was confirmed by RT-qPCR and Western blot, and functional assays showed increased FAO activity and ferroptosis resistance in NOTCH3 ICD-expressing cells compared to controls.

Key Findings

• NOTCH3 expression is elevated in aggressive meningioma tumors and cell lines.
• NOTCH3 activation leads to depletion of intracellular fatty acids, indicating enhanced fatty acid oxidation.
• Enhanced FAO mediated by NOTCH3 protects meningioma cells from ferroptosis-induced cell death.
• NOTCH3-driven metabolic reprogramming may contribute to tumor growth and resistance to therapies such as radiation.
• NOTCH3 represents a potential therapeutic target to disrupt metabolic adaptations in aggressive meningiomas.

Clinical Implications

Targeting NOTCH3 signaling or its downstream metabolic pathways, such as fatty acid oxidation, may sensitize aggressive meningiomas to ferroptosis and improve therapeutic outcomes. Understanding the metabolic phenotype driven by NOTCH3 could guide the development of novel treatments aimed at overcoming resistance mechanisms in meningioma patients.

Conclusion

NOTCH3 enhances fatty acid oxidation in meningioma cells, conferring resistance to ferroptosis and promoting tumor aggressiveness. These findings highlight NOTCH3 as a promising target for metabolic intervention in aggressive meningiomas.

References

1. Choudhury et al. 2023 -- NOTCH3 as a driver of tumor growth and radiation resistance in meningiomas
2. Cell Signaling Technology -- Antibodies for NOTCH3 and GAPDH