Proteogenomic Insights Into Glioblastoma Evolution: Neuronal Reprogramming and Therapeutic Vulnerabilities

Area of Science:

• Neuro-oncology
• Cancer Biology
• Proteogenomics

Background:

• Glioblastoma (GBM) is a lethal brain cancer with high recurrence rates.
• Previous studies identified patient-specific evolution but not conserved drivers of resistance.
• A gap existed in understanding the biological programs underlying GBM recurrence and treatment failure.

Purpose of the Study:

• To conduct the first integrated proteogenomic analysis of matched primary and recurrent GBMs.
• To identify conserved biological programs driving GBM recurrence and therapeutic resistance.
• To contextualize findings within GBM evolution and explore therapeutic vulnerabilities.

Main Methods:

• Integrated proteogenomic, transcriptomic, and phosphoproteomic analysis of matched primary and recurrent GBM samples.
• Comparative analysis to identify phenotypic transitions and underlying molecular mechanisms.
• Review and contextualization of findings with existing GBM evolution literature and preclinical models.

Main Results:

• Recurrent GBM tumors exhibit a significant phenotypic transition towards a neuronal-like state.
• This transition is supported by coordinated transcriptional, proteomic, and phosphoproteomic changes.
• WNT/planar cell polarity (PCP) signaling and BRAF kinase activation were identified as key drivers of this neuronal reprogramming.

Conclusions:

• Neuronal reprogramming enhances GBM plasticity, invasion, and treatment resistance.
• Proteogenomics provides a powerful approach to uncover actionable vulnerabilities in recurrent GBM.
• These findings establish a new framework for biomarker discovery and targeted therapy design informed by tumor evolution and neuronal niche adaptation.