Richard Drexler, Robin Khatri, Thomas Sauvigny, Malte Eberhard Mohme, Cecile Maire, Alice Ryba, Yahya Zghaibeh, Lasse Duhrsen, Amanda Salviano-Silva, Katrin Lamszus, Manfred Westphal, Jens Gempt, Annika K. Wefers, Julia Neumann, Helena Bode, Fabian Hausmann, Tobias Huber, Stefan Bonn, Kerstin Maria Jütten, Daniel I. Delev, Katharina J. Weber, Patrick Nikolaus Harter, Julia Sophie Onken, Peter Vajkoczy, David Capper, Benedikt Wiestler, Michael Weller, Berend Snijder, Alicia Buck, Tobias Weiss, Michael B. Keough, Lijun Ni, Michelle Monje, Dana Silverbush, Volker Hovestadt, Mario L. Suva, Saritha Krishna, Shawn Hervey-Jumper, Ulrich Schüller, Henrik Dieter Heiland, Sonja Hänzelmann, Franz Lennard Ricklefs
- Neural-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 formation in vitro and in vivo and 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.
