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

Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms behind this evolution is vital for effective therapies. While treatment resistance is associated with glioblastoma's intratumoral heterogeneity, it remains uncertain if hypometabolic and hypermetabolic lesions observed through 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 imaging technologies, followed by comprehensive whole-genome/exome and transcriptome analysis. Our findings reveal that hypermetabolic lesions evolve from hypometabolic lesions, harbor shrewd focal amplifications and deletions, and exhibit a higher frequency of critical genomic alterations linked to increased aggressiveness. We also found gene signatures in hypermetabolic lesions, including upregulated APOBEC3, hypoxic genes, and downregulated putative tumor suppressors. This study highlights a spatial genomic evolution with diagnostic implications and unveils obstacles and possibilities that should be considered in the development of novel therapeutic strategies.