Serotonergic neuron-glioma interactions drive high-grade glioma pathophysiology
Year: 2025
Type: preprint
Abstract: High-grade gliomas are lethal brain cancers that are powerfully regulated by glutamatergic neurons through activity-dependent paracrine factors and functional neuron-to-glioma synapses. Here, we report that serotonergic neurons promote the proliferation of high-grade gliomas throughout the brain. Serotonergic neuronal activity drives circuit-specific increases in high-grade glioma proliferation, calcium transients, and reduced survival. This growth-promoting effect is chiefly mediated by activation of the serotonin (5-hydroxytryptamine; 5HT) receptor 5HT 2A on glioma cells. Knock out or pharmacological blockade of 5HT 2A receptors in glioma abrogated the glioma growth-promoting effects of serotonergic neuronal activity, while serotonergic psychedelic drugs robustly promote malignant cell proliferation. Gliomas alter serotonergic neuronal activity patterns, resulting in elevated serotonin release into the tumor microenvironment. Together, these findings uncover pathogenic, feed-forward interactions between serotonergic neurons and glioma cells.
Authors: Richard Drexler, Belgin Yalçın, Rebecca Mancusi, Abigail Rogers, Kiarash Shamardani, Pamelyn J. Woo, Alexandre Ravel, Samuel Wu, Yahaya A. Yabo, Lisa Steger, Carlos Alberto Oliveira de Biagi-Junior, Costanza Lo Cascio, Robert Malenka, Boris D. Heifets, Mariella G. Filbin, Dieter Henrik Heiland, Karl Deisseroth, Michelle Monje
Institutions: Stanford University, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Dana-Farber Cancer Institute, Harvard University, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Stanford Medicine, Northwestern University, Howard Hughes Medical Institute
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: How the 3D Architecture of the Brain Shapes Cancer Cell Fate Decisions, eDyNAmiC - STANFORD, Neuronal activity-regulated mechanisms of glioma growth, Glioma Circuitry: Bridging Systems Neuroscience and Cancer, Neuronal Regulation of Low-Grade Gliomagenesis, Leveraging innovative technologies in basic and clinical cancer research, Targeted Therapies for Glioma, Neural circuit dynamics of drug action:revealing, uncoupling, and restoring altered brain states, Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma
OpenAlex ID: W4417287256