Abstract
Glioma cells form multicellular communication networks through tumour microtubes (TMs), integrating tumour-tumour and neuron-tumour connectivity to sustain growth and therapy resistance. Underlying molecular regulation of TMs and potential targeting strategies have proven elusive. Here, we demonstrate that glioma stem cells (GSCs) preferentially grow TMs, which locally synthesize neurotransmitter receptors and metabolic enzymes to support network communication. Coordinated proteomics and functional screening of TMs identified inner mitochondrial component, FASTKD2, as essential to local protein synthesis. Targeting FASTKD2 attenuates tumour stemness and growth, disrupting coordinated mitochondrial RNA metabolism in TMs, which sustains intercellular communication and tumour proliferation. Structure-function screening revealed antibiotic linezolid inhibited FASTKD2 interactions with mitochondrial RNA, thereby disrupting tumour network communication and augmenting efficacy of therapies targeting neuronal stimulation of tumour cells. Collectively, tumour cells coopt features of neuronal cell biology, including localized protein synthesis, to reinforce TM-mediated glioma network communication, generating therapeutic vulnerabilities.