Targeting PGE2 mediated senescent neuron improves tumor therapy.

Area of Science:

• Neuro-oncology
• Cancer biology
• Molecular mechanisms of therapy resistance

Background:

• Tumor-neuron signaling is crucial but poorly understood in the context of radio-/chemotherapy.
• Obscure tumor-neuron interactions hinder effective glioblastoma treatment strategies.

Purpose of the Study:

• To elucidate the mechanisms of neuron-tumor interactions during radio-/chemotherapy.
• To identify therapeutic targets for improving glioblastoma treatment.

Main Methods:

• Glioblastoma organoids (GBOs) and primary neuron co-cultures were used.
• Techniques included metabonomics, RNA sequencing, mass spectrometry, and in vivo mouse models.
• Diagnostic and prognostic values were assessed in patient data (serum, tissue microarrays, TCGA).

Main Results:

• Tumor-derived prostaglandin E2 (PGE2) induced neuronal senescence post-therapy.
• Asparagine endopeptidase (AEP) cleaved eIF4A1, stabilizing PTGES3 mRNA and increasing PGE2.
• Inhibiting PGE2 or AEP reduced senescence and delayed tumor progression; high PTGES3 correlated with poor prognosis.

Conclusions:

• A feedback loop involving AEP and PGE2 drives tumor-induced neuronal senescence during radio-/chemotherapy.
• This pathway represents a potential therapeutic target to enhance glioblastoma treatment.