Epigenetic neural glioblastoma enhances synaptic integration and predicts therapeutic vulnerability

Author:

Drexler Richard,Khatri Robin,Sauvigny Thomas,Mohme Malte,Maire Cecile L.,Ryba Alice,Zghaibeh Yahya,Dührsen Lasse,Salviano-Silva Amanda,Lamszus Katrin,Westphal Manfred,Gempt Jens,Wefers Annika K.,Neumann Julia,Bode Helena,Hausmann Fabian,Huber Tobias B.,Bonn Stefan,Jütten Kerstin,Delev Daniel,Weber Katharina J.,Harter Patrick N.,Onken Julia,Vajkoczy Peter,Capper David,Wiestler Benedikt,Weller Michael,Snijder BerendORCID,Buck Alicia,Weiss Tobias,Keough Michael B.,Ni Lijun,Monje Michelle,Silverbush Dana,Hovestadt Volker,Suvà Mario L.,Krishna Saritha,Hervey-Jumper Shawn L.,Schüller Ulrich,Heiland Dieter H.ORCID,Hänzelmann Sonja,Ricklefs Franz L.

Abstract

ABSTRACTNeural-tumor interactions drive glioma growth as evidenced in preclinical models, but clinical validation is nascent. We present an epigenetically defined neural signature of glioblastoma that independently affects patients’ survival. We use reference signatures of neural cells to deconvolve tumor DNA and classify samples into low- or high-neural tumors. High-neural glioblastomas exhibit hypomethylated CpG sites and upregulation of genes associated with synaptic integration. Single-cell transcriptomic analysis reveals high abundance of stem cell-like malignant cells classified as oligodendrocyte precursor and neural precursor cell-like in high-neural glioblastoma. High-neural glioblastoma cells engender neuron-to-glioma synapse formationin vitroandin vivoand show an unfavorable survival after xenografting. In patients, a high-neural signature associates with decreased survival as well as increased functional connectivity and can be detected via DNA analytes and brain-derived neurotrophic factor in plasma. Our study presents an epigenetically defined malignant neural signature in high-grade gliomas that is prognostically relevant.

Publisher

Cold Spring Harbor Laboratory

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