Neuronal Activity Promotes Glioma Progression by Inducing Proneural-to-Mesenchymal Transition in Glioma Stem Cells

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Abstract
Neuronal activity can drive progression of high-grade glioma by mediating mitogen production and neuron-glioma synaptic communications. Glioma stem cells (GSC) also play a significant role in progression, therapy resistance, and recurrence in glioma, which implicates potential cross-talk between neuronal activity and GSC biology. Here, we manipulated neuronal activity using chemogenetics in vitro and in vivo to study how it influences GSCs. Neuronal activity supported glioblastoma (GBM) progression and radioresistance through exosome-induced proneural-to-mesenchymal transition (PMT) of GSCs. Molecularly, neuronal activation led to elevated miR-184–3p in neuron-derived exosomes that were taken up by GSCs and reduced the mRNA N6-methyladenosine (m6A) levels by inhibiting RBM15 expression. RBM15 deficiency decreased m6A modification of DLG3 mRNA and subsequently induced GSC PMT by activating the STAT3 pathway. Loss of miR-184–3p in cortical neurons reduced GSC xenograft growth, even when neurons were activated. Levetiracetam, an antiepileptic drug, reduced the neuronal production of miR-184–3p-enriched exosomes, inhibited GSC PMT, and increased radiosensitivity of tumors to prolong survival in xenograft mouse models. Together, these findings indicate that exosomes derived from active neurons promote GBM progression and radioresistance by inducing PMT of GSCs. Significance: Active neurons secrete exosomes enriched with miR-184–3p that promote glioblastoma progression and radioresistance by driving the proneural-to-mesenchymal transition in glioma stem cells, which can be reversed by antiseizure medication levetiracetam.
Funding Information
  • Fundamental Research Funds for the Central Universities (2022JC019)
  • National Natural Science Foundation of China (82072776, 82273195)
  • National Natural Science Foundation of China (82072775, 82273286)
  • National Natural Science Foundation of China (82203419)
  • Natural Science Foundation of Shandong Province (ZR2021LSW025)
  • Jinan Science and Technology Bureau (2021GXRC029)
  • Taishan Pandeng Scholar Program of Shandong Province (tspd20210322)
  • Taishan Scholar Program of Shandong Province (tsqn202211316)
  • Science and Technology Innovation Major Project, Ministry of Science and Technology of China (2021ZD0201600)

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