Spatial Multiomics Defines a Shared Tumor Infiltrative Signature at the Resection Margin in High-Grade Gliomas.

Area of Science:

• Neuro-oncology
• Genomics
• Molecular Biology

Background:

• High-grade gliomas (HGG) exhibit diffuse infiltration, hindering surgical resection and leading to recurrence.
• Current understanding of HGG biology relies heavily on "core" tumor tissue, neglecting the poorly defined resection margin where residual disease resides.

Purpose of the Study:

• To investigate the molecular differences and shared characteristics between the "core" and "margin" of high-grade gliomas.
• To identify key molecular drivers of glioma infiltration at the tumor margin.

Main Methods:

• Generated a multi-omic dataset using single-nucleus RNA sequencing (snRNA-seq) and single-nucleus Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq) from matching HGG "core" and "margin" dissections.
• Integrated spatial transcriptomics data and performed computational analyses including differential expression, chromatin accessibility, cell-cell interactions, and transcription factor activity.
• Utilized RNA velocity and pseudotime analysis to reconstruct the core-to-margin transition.

Main Results:

• Identified a unique, shared "glioma infiltration" signature present in the tumor margin across diverse HGG subtypes.
• Epidermal growth factor receptor (EGFR) emerged as a top differentially expressed and accessible marker at the tumor margin, showing dynamic expression along the infiltration trajectory.
• CRISPR/Cas9-mediated EGFR deletion validated its role in migration, and TEAD1 was implicated as a transcriptional regulator of EGFR at the margin.

Conclusions:

• The study defines a molecular signature associated with glioma infiltration at the tumor margin.
• EGFR is a critical marker and potential therapeutic target for controlling HGG spread and recurrence.
• This multi-omic resource provides insights into residual disease biology and the tumor microenvironment at the infiltrative margin.