Metabolic Profiling of Meningioma Reveals Novel Subgroup-Specific Biologic Insights and Outcome Dependencies

Background: Prior studies have elucidated the presence of four consensus molecular groups (MGs) of meningioma, with unique underlying biology and outcomes. The hyperactivation of metabolic pathways may be associated with tumor growth, and therefore poor outcomes, in the so-called hypermetabolic (MG3) tumors, and there is a need to better understand the metabolic landscape of these tumors. This study is the first to study the global metabolon of meningioma in the context of modern molecular subgroups.

Methods: Untargeted metabolic profiling (Metabolon Inc.) was performed on 53 meningiomas representing each molecular group and WHO grade. Prognostic biochemicals were identified using Cox regression and further investigated using RNA and protein-based pathway analyses. A larger cohort with available RNA sequencing (n = 121) was used to further explore the prognostic influence of relevant pathways, and biochemicals of interest were validated on a subset of these samples (n = 35) using targeted high performance liquid chromatography-mass spectrometry (HPLC-MS/MS).

Results: Global metabolic profiling identified 560 unique biochemicals for downstream analysis. The abundance of N6-trimethyllysine was associated with significantly earlier time to recurrence highly prognostic on our whole cohort (HR [95%CI] = 3.18 [1.45–26.23], p = 0.004) and within hypermetabolic (MG3) tumors (HR [95% CI] = 6.73 [1.72–6.97], p = 0.006); pyruvate was associated with worse outcomes in proliferative (MG4) tumors specifically (HR [95%CI] = 5.65 [1.073–29.71], p = 0.041). Analysis of implicated gene pathways demonstrated that upregulation of the oxidative phosphorylation pathway portends worse outcomes in the hypermetabolic subgroup but, surprisingly, better outcomes in the proliferative subgroup. By contrast, upregulated lactate transporters were associated with worse outcomes in proliferative, but not hypermetabolic, meningiomas.

Conclusion: This is the first study to demonstrate a subgroup-specific prognostic role of N6-trimethyllysine and pyruvate in meningioma, offering increasingly granular outcome predictions using a widely accessible technique (HPLC-MS/MS). In addition, we demonstrated key differences in energy utilization between hypermetabolic and proliferative tumors, both of which are associated with poor outcomes, suggesting fundamental differences in preferred energy utilization and reinforcing a need for subgroup-specific therapies.

Publikationsverlauf

Artikel online veröffentlicht:
07. Februar 2025