PLA2 driven lipid signaling drives ARMS tumorigenic cell properties

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Alveolar rhabdomyosarcoma (ARMS) has poor relapse-free survival despite chemotherapy advances.
• Tumor-initiating cells (TICs) drive ARMS recurrence, but their characteristics are poorly understood.
• Lipid metabolism is increasingly recognized for its role in cancer stemness.

Purpose of the Study:

• To investigate the transcriptomic and metabolic profiles of TICs in ARMS.
• To explore the role of lipid metabolism in ARMS TIC maintenance and function.
• To assess the therapeutic potential of targeting lipid metabolism in ARMS.

Main Methods:

• Transcriptomic and lipidomic profiling of ARMS tumorsphere and adherent cells.
• RNA-Sequencing and mass spectrometry to identify differentially expressed genes and lipids.
• In vitro and in vivo functional assays to evaluate the impact of Phospholipase A2 (PLA2) inhibition.

Main Results:

• ARMS TICs exhibit upregulated lipid metabolism, particularly PLA2 enzyme subtypes, and suppressed glycolysis.
• Enrichment of linoleic acid-derived lipids and increased PLA2 activity were observed in TICs.
• PLA2 inhibition reduced ARMS TIC self-renewal, motility, and tumor growth, effects rescued by linoleic acid.

Conclusions:

• PLA2-mediated lipid remodeling supports ARMS TICs via linoleic acid signaling.
• PLA2 inhibition represents a promising therapeutic strategy for targeting the ARMS stem-like compartment.
• Lipid remodeling is a critical metabolic adaptation in ARMS TICs, independent of conventional energy pathways.