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Small Extracellular Vesicles from Radioresistant H3K27M-Pediatric Diffuse Midline Glioma Cells Modulate Tumor

Viral D Oza1,2, Kenan A Flores1, Yelena Chernyavskaya1

  • 1Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.

Biorxiv : the Preprint Server for Biology
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Summary

Pediatric diffuse midline gliomas (H3K27M-pDMG) resist radiation therapy. Small extracellular vesicles (sEVs) from radioresistant tumors protect sensitive cells, suggesting sEVs drive H3K27M-pDMG radiation resistance.

Keywords:
DIPGDNA repairdiffuse midline gliomaextracellular vesiclesglioma stem cellsmiRNAoxidative phosphorylationradiation therapy

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Area of Science:

  • Neuro-oncology
  • Cancer biology
  • Cellular communication

Background:

  • Pediatric diffuse midline gliomas (H3K27M-pDMG) are aggressive brain tumors.
  • H3K27M-pDMG exhibit intrinsic resistance to radiation therapy.
  • Intratumoral heterogeneity and small extracellular vesicles (sEVs) may contribute to therapy resistance.

Purpose of the Study:

  • Investigate the role of sEVs in H3K27M-pDMG radiation resistance.
  • Characterize sEV uptake and identify key sEV surface proteins.
  • Determine if sEVs from radioresistant cells confer protection to radiosensitive cells.

Main Methods:

  • Characterized sEV uptake dynamics in H3K27M-pDMG cells.
  • Identified key sEV surface proteins.
  • Performed molecular profiling of sEVs (proteins, miRNAs, metabolites).
  • Assessed gene expression, metabolic pathways, DNA repair, and survival post-radiation.

Main Results:

  • sEVs from radioresistant H3K27M-pDMG cells protected radiosensitive cells from radiation.
  • RR-sEVs carry cargo (proteins, miRNAs, metabolites) linked to glycolysis, oxidative phosphorylation, and DNA repair.
  • Uptake of RR-sEVs reprogrammed recipient cells, enhancing survival and DNA repair post-radiation.

Conclusions:

  • sEV-mediated communication contributes to radiation resistance in H3K27M-pDMG.
  • RR-sEVs reprogram recipient cells to promote survival and DNA repair.
  • Targeting sEV-mediated communication may enhance radiation therapy efficacy for H3K27M-pDMG.