# Multiomic profiling of glioblastoma metabolic lesions reveals complex intratumoral genomic evolution and dipeptidase-1-driven vascular proliferation

## TL;DR

This study shows how glioblastoma tumors evolve by comparing hypometabolic and hypermetabolic regions, revealing new insights into tumor metabolism and potential treatment targets.

## Contribution

The study identifies dipeptidase-1 as a novel vascular marker and reveals spatial genomic evolution in glioblastoma.

## Key findings

- Hypermetabolic lesions show focal genomic changes and increased APOBEC3 activity.
- Dipeptidase-1 is a novel vascular marker linked to angiogenesis and tumor metabolism.
- Hypermetabolic lesions have more genomic abnormalities than hypometabolic ones.

## Abstract

Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through clinical positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution.

In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome, exome, transcriptome, and imaging analyses.

Our findings unveil that hypermetabolic lesions, originating from hypometabolic lesions, exhibit strategic focal amplifications and deletions, and heightened APOBEC3 activity. Furthermore, we identify dipeptidase 1 as a novel vascular endothelial tip marker for hypermetabolic lesions in glioblastoma, facilitating angiogenesis and tumor metabolism by regulating transporter activities.

Hypermetabolic lesions are associated with a higher frequency of genomic abnormalities and dipeptidase 1 emerges as a novel diagnostic and prognostic vascular marker for hypermetabolic lesions. This study underscores a spatial genomic evolution with diagnostic implications and elucidates challenges and opportunities crucial for the development of novel therapeutic strategies.

Graphical Abstract