#South Korea #Seoul #Korea University #Meningioma #COL6A3

Exploring the Evolutionary Trajectory of Meningiomas

Meningiomas represent the most prevalent form of primary brain tumor, comprising roughly one-third of all central nervous system (CNS) tumors. While the majority of these tumors are benign and treatable, a troubling 20-30% progress into high-grade variants that exhibit aggressive behavior, frequent recurrence, and resistance to standard therapies. The challenge posed by recurrent meningiomas is significant, as these tumors can often return more resilient than before, offering patients limited options for treatment. Despite advancements in genetic and molecular profiling in the field, little has been understood about the evolutionary transition of meningiomas from their primary state to recurrence.

To tackle this important question, a research team from Korea University set out to create a comprehensive map of how meningiomas evolve at the single-cell level. The study aimed to investigate not only how tumor cells evolve over time, but also how their surrounding microenvironment changes between the primary and recurrent stages of disease. The lead author, Associate Professor Jason K. Sa, emphasized the groundbreaking nature of their findings, stating, "We generated the first longitudinal single-cell atlas of matched primary and recurrent meningiomas. This valuable resource allowed us to reconstruct the tumor evolution trajectories and cellular hierarchies across time, revealing significant shifts in proliferative programs and tumor–immune interactions upon recurrence."

Published on July 1, 2025, in Nature Communications, the study utilized single-nuclei RNA sequencing (snRNA-seq) to analyze matched patient samples, which provided an in-depth profile of both the tumor cells and their surrounding environment. The application of RNA velocity and latent time analyses enabled the team to track transcriptional changes throughout the tumor's progression toward recurrence, with further validation obtained through external RNA-seq datasets and immunohistochemistry (IHC) techniques, bolstering the study's findings.

The research unveiled substantial insights into the behavior of recurrent meningiomas, which displayed dramatically higher levels of proliferative activity compared to their primary forms, particularly highlighting an enrichment of processes related to the cell cycle. Instead of a straightforward progression, recurrent tumors diverged into several aggressive transcriptional trajectories. Notably, the research team pinpointed COL6A3 as a key player in driving these changes. The first author, Ms. Ji Yoon Lee, stated, "We identified COL6A3 as a vital driver of meningioma recurrence, closely associated with relapse risk and treatment resistance. An analysis of tumor cell and macrophage interactions revealed that the COL6A3-CD44 signaling cascade not only mediates extracellular matrix remodeling but also creates an immunosuppressive tumor environment upon recurrence."

This dual role of COL6A3 makes it an attractive target for therapeutic interventions. Dr. Sa elaborated, saying, "Identifying COL6A3 as a driver of malignancy in recurrent meningiomas underscores its potential. First, as a prognostic biomarker, it might help better stratify high-risk patients and inform treatment decisions. Second, it presents a novel target for drug discovery, leading to precision strategies that could combine early diagnostics with targeted therapies to enhance patient outcomes."

The implications of this research significantly enhance the understanding of meningioma progression from primary to recurrent states. It stresses the importance of addressing both tumor cell evolution and the evolving tumor–immune interactions as critical components in the therapeutic design process. Looking forward, Ms. Lee mentioned, "We anticipate that within the next 5 to 10 years, this research could revolutionize patient care by providing predictive tools for assessing radiotherapy response and recurrence risk. Ultimately, targeting COL6A3 might emerge as a promising approach to prevent recurrences and improve prognoses for those suffering from high-grade meningiomas."

Reference

• - Title of Original Paper: Single-cell analysis reveals a longitudinal trajectory of meningioma evolution and heterogeneity
• - Journal: Nature Communications
• - DOI: 10.1038/s41467-025-60653-0

About Korea University College of Medicine

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