Remote neuronal activity drives glioma progression through SEMA4F

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

Nature, 2023, vol. 619, issue 7971, 844-850

Abstract: Abstract The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3–8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours 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 tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.

Date: 2023
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DOI: 10.1038/s41586-023-06267-2

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