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Transformation Foci in IDH1-mutated Gliomas Show STAT3 Phosphorylation and Downregulate the Metabolic Enzyme ETNPPL,

N Leventoux1,2, M Augustus1, S Azar1

  • 1Institute for Neurosciences of Montpellier, Institut National de la Santé et de la Recherche Médicale (INSERM). U1051 - Hôpital Saint-Éloi, 80 Avenue Augustin Fliche - 34091 Montpellier cedex 5, Montpellier, France.

Scientific Reports
|March 29, 2020
PubMed

Insights

Early molecular changes in IDH1-mutated gliomas involve altered lipid metabolism and JAK/STAT signaling activation. Reduced Ethanolamine-Phosphate Phospho-Lyase (ETNPPL) expression promotes glioma progression, while its overexpression inhibits growth.

Area of Science:

  • Neuro-oncology
  • Molecular Biology
  • Cancer Research

Background:

  • IDH1-mutated gliomas are slow-growing tumors with poorly understood malignant progression.
  • Transformation foci within these tumors offer insights into early molecular events driving progression.

Purpose of the Study:

  • To characterize the molecular alterations in transformation foci of IDH1-mutated gliomas.
  • To identify key molecular pathways and enzymes involved in glioma progression.

Main Methods:

  • Immunohistochemistry and high-throughput RNA profiling were employed to analyze foci cells.
  • Expression levels of specific RNAs and proteins, including ETNPPL, were assessed.

Main Results:

  • Foci cells exhibited increased pSTAT3 staining, indicating JAK/STAT pathway activation.
  • Downregulation of RNAs involved in Wnt and EGFR signaling, cytoskeleton, and cell-cell communication was observed.
  • Reduced levels of Ethanolamine-Phosphate Phospho-Lyase (ETNPPL/AGXT2L1), a lipid metabolism enzyme, were found in foci cells and inversely correlated with glioma grade.
  • ETNPPL protein was detected in glioma cells and astrocytes, with nuclear localization suggesting additional functions.

Conclusions:

  • Combined alterations in membrane lipid metabolism (reduced ETNPPL) and STAT3 pathway activation promote malignant progression in IDH1-mutated gliomas.
  • ETNPPL acts as a tumor suppressor, opposing gliomagenesis, as evidenced by its reduced expression in high-grade gliomas and inhibitory effect on glioma stem cell growth.

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