Remote Neuronal Activity Drives Glioma Progression Through SEMA4F

Authors

Emmet Huang-Hobbs
Yi-Ting Cheng
Yeunjung Ko
Estefania Luna-Figueroa
Brittney Lozzi
Kathryn R Taylor
Malcolm McDonald
Peihao He
Hsiao-Chi Chen
Yuhui Yang
Ehson Maleki
Zhung-Fu Lee
Sanjana Murali
Michael R Williamson
Dongjoo Choi
Rachel Curry
James Bayley
Junsung Woo
Ali Jalali
Michelle Monje
Jeffrey L Noebels
Akdes Serin Harmanci
Ganesh Rao
Benjamin Deneen

Publication Date

7-1-2023

Journal

Nature

DOI

10.1038/s41586-023-06267-2

PMID

37380778

PMCID

PMC10840127

PubMedCentral® Posted Date

2-5-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Brain, Brain Neoplasms, Carcinogenesis, Cell Line, Tumor, Cell Transformation, Neoplastic, Glioblastoma, Glioma, Neurons, Tumor Microenvironment, Cell Proliferation, Synapses, Disease Progression, Animals, Mice, Axons, Corpus Callosum, Neural Pathways

Abstract

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent progression. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of glioma progression that are regulated by neuronal activity.