# Natural progression of glioma enhances functional connection with the cerebral cortex through synaptogenesis

## TL;DR

This study shows that as gliomas grow, they form stronger connections with the cerebral cortex through synaptogenesis, using patient data and mouse models.

## Contribution

The study reveals that glioma progression is linked to increased cortical connectivity and synaptogenesis, supported by multimodal and cross-scale analysis.

## Key findings

- Larger tumors in multifocal gliomas show stronger functional connectivity with the cerebral cortex.
- Synaptic organization and regulatory pathways are progressively activated during glioma progression.
- Functional hyperconnectivity is supported by microscale molecular programs driving synaptogenesis.

## Abstract

•Multifocal glioma patients and mouse models help address the lack of longitudinal data in untreated patients.•In multifocal gliomas, larger tumors exhibit stronger cortical functional connectivity and higher degree centrality.•During glioma progression, synaptic organization and associated pathways are progressively activated.

Multifocal glioma patients and mouse models help address the lack of longitudinal data in untreated patients.

In multifocal gliomas, larger tumors exhibit stronger cortical functional connectivity and higher degree centrality.

During glioma progression, synaptic organization and associated pathways are progressively activated.

Understanding the progression mechanisms of glioma holds significant implications for improving clinical management. However, the natural progression patterns of glioma remain poorly understood due to the lack of longitudinal clinical samples from untreated patients.

In this study, we systematically explored the natural progression trajectory of glioma by combining functional magnetic resonance imaging (fMRI) analysis of 24 rare multifocal glioma patients with bioinformatic analysis of single-cell RNA sequencing (scRNA-seq) data obtained from tumor samples of glioma mouse with early, mid, and endpoint lesions.

We discovered that larger tumors in multifocal gliomas exhibit stronger functional connectivity with the cerebral cortex and higher degree centrality within brain networks. ScRNA-seq of longitudinal mouse glioma samples revealed progressive activation of synaptic organization and associated regulatory pathways during the natural progression of glioma.

Our multimodal, cross-scale study demonstrates that the natural progression pattern of glioma macroscopically manifests as functional hyperconnectivity with the cerebral cortex, which is supported by microscale molecular programs driving synaptogenesis. These findings elucidate the characteristics and mechanisms underlying glioma natural progression.