Neural "brake" found to suppress brain tumor growth and improve survival in mice

Since the emergence of the field of cancer neuroscience around 2015, neuronal activity has generally been viewed as a driver of cancer growth and invasion. A collaborative research team led by Professor Daisuke Kawauchi of the Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Professor Naofumi Uesaka of the Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Division Chief Reo Maruyama of the Division of Cancer Epigenomics at the Cancer Institute of the Japanese Foundation for Cancer Research, and Specially Appointed Professor Masanobu Kano and Lecturer Takaki Watanabe of Teikyo University's Advanced Comprehensive Research Organization has revealed that inhibitory neural circuits in the brain reduce calcium activity in adult glioma cells, including glioblastoma, and suppress the YAP1-mTOR signaling pathway. The study provides the first evidence that neural circuits can act not only as an accelerator, but also as a brake on brain tumor growth.

Professor Kawauchi said, "In mouse models of brain tumors, activating inhibitory neurons improved survival. We hope to translate this finding into a new therapeutic approach that creates an environment less conducive to cancer growth." Adult glioma is a highly invasive brain tumor that is difficult to treat and often recurs even after surgical removal.

Tumor cells do not grow in isolation but are influenced by their surrounding environment, including neurons and blood vessels. In particular, a growing body of research has shown that neuronal electrical activity and neurotransmitters promote the growth of brain tumor cells, driving the development of the field of cancer neuroscience.

Previous studies have focused mainly on excitatory neural circuits that promote tumor growth, while the effects of inhibitory neural circuits, which suppress neuronal activity, have remained poorly understood. Professor Kawauchi explained, "Our initial idea was simple: if excitatory neurons activate tumors, perhaps inhibitory neurons could suppress them."

The researchers therefore sought to determine whether inhibitory neurons directly transmit signals to adult glioma cells and how those signals regulate calcium activity and tumor growth. First, through electron microscopy and electrophysiological analyses, the team showed that adult glioma cells, including glioblastoma cells, receive direct synaptic input from inhibitory neurons in the brain. This input acted to suppress the electrical activity of the tumor cells.

Next, when inhibitory neuronal activity was enhanced in the brains of mice, both the intensity and spatial spread of calcium activity within tumor cells decreased, resulting in reduced tumor growth. As a result, the survival of tumor-bearing mice was prolonged. Conversely, reducing inhibitory neuronal activity promoted tumor growth. Furthermore, directly suppressing calcium activity in tumor cells also reduced tumor growth and extended survival. In contrast, artificially restoring calcium activity within tumor cells weakened the tumor-suppressive effect of inhibitory neuronal activity.

These findings demonstrated a causal relationship in which inhibitory neural circuits suppress calcium activity in tumor cells, thereby limiting tumor growth. At the molecular level, reduced calcium activity was accompanied by suppression of the YAP1 and mTOR signaling pathways, which are involved in tumor growth and survival. The researchers also confirmed that inhibitory neuronal activity suppresses tumor cell proliferation in human-derived glioma models established from patient tumor tissues. Together, these findings demonstrate that inhibitory neural circuits function as a brake within the brain against adult glioma.

By tracing the mechanism from calcium signaling in tumor cells to activation of the YAP1 and mTOR pathways, the study provides a comprehensive picture of how neuronal activity influences brain tumors. The findings add a new perspective to cancer neuroscience by showing that neural circuits can function not only as accelerators, but also as brakes on tumor progression.

Professor Kawauchi commented, "We believe this achievement was possible because of the collaborative efforts of researchers from nine institutions, each bringing their own expertise to the project. Conducting all of the experiments in living mice rather than in cultured cells was the most challenging aspect of the study. We believe similar mechanisms may exist in other types of cancer as well, and are currently investigating this possibility."

Journal Information
Publication: Neuron
Title: Inhibitory circuits restrain adult glioma progression by suppressing calcium-driven oncogenic programs
DOI: 10.1016/j.neuron.2026.08.008