Meningiomas are the most common primary brain tumors, accounting for nearly one-third of all central nervous system (CNS) tumors. While most are benign and manageable, 20–30% progress to high-grade forms that behave aggressively, recur frequently, and resist standard treatments. Recurrence remains a major clinical challenge, as these tumors often return stronger, leaving patients with limited therapeutic options. Despite advances in understanding their genetic and molecular profiles, how meningiomas evolve from primary to recurrent states has remained unclear.
To address this gap, researchers from Korea University set out to map the evolutionary trajectory of meningiomas at single-cell resolution. Their goal was to investigate how tumor cells and their microenvironment evolve between primary and recurrent disease, and to identify the molecular drivers of recurrence. Lead author Associate Professor Jason K. Sa explains: “Our study generated the first longitudinal single-cell atlas of matched primary and recurrent meningiomas. This resource enabled us to reconstruct tumor evolutionary trajectories and cellular hierarchies over time, revealing profound shifts in proliferative programs and tumor–immune interactions at recurrence.” Their findings were published in Nature Communications on July 1, 2025.
The team analyzed matched patient samples using single-nuclei RNA sequencing (snRNA-seq), which allowed profiling of both tumor cells and their surrounding microenvironment. To capture the dynamic progression of tumor cells, they applied RNA velocity and latent time analysis, tracking transcriptional changes as tumors transitioned to recurrence. Findings were further validated using external RNA-seq datasets and immunohistochemistry (IHC), strengthening the robustness of the results.
The study uncovered several key insights. Recurrent meningiomas exhibited markedly higher proliferative activity compared to their primary counterparts, which were enriched in cell cycle–related processes. Rather than progressing linearly, recurrent tumors diverged into multiple aggressive transcriptional trajectories. Most notably, the researchers identified COL6A3 as a central player driving these transitions.
“We identified COL6A3 as a key driver of meningioma recurrence, associated with relapse risk and treatment resistance. Further analysis of tumor cell–macrophage interactions revealed that the COL6A3–CD44 signaling cascade mediates extracellular matrix remodeling and promotes an immunosuppressive tumor microenvironment at recurrence,” Ms. Ji Yoon Lee, the study’s first author, notes. This dual role in both tumor cell behavior and immune modulation makes COL6A3 an especially compelling therapeutic target.
Dr. Sa adds, “By identifying COL6A3 as a driver of malignancy in recurrent meningiomas, we found its dual potential. First, as a prognostic biomarker to better stratify high-risk patients and guide treatment decisions, and second, as a novel therapeutic target for drug discovery. This opens the door to precision strategies that combine early diagnosis with targeted therapies to improve patient outcomes.”
This work significantly advances our understanding of how meningiomas progress from primary to recurrent states. It emphasizes the need to address both tumor cell evolution and tumor–immune interactions when designing therapies. Looking ahead, Ms. Lee shares: “Over the next 5 to 10 years, we anticipate this work can impact patient care by enabling predictive tools for radiotherapy response and recurrence risk assessment.”
Ultimately, targeting COL6A3 may provide a promising strategy to prevent recurrence and improve outcomes for patients with high-grade meningiomas.
***
Reference
DOI: 10.1038/s41467-025-60653-0
About Korea University College of Medicine
Korea University College of Medicine is the medical school of Korea University. It is located in Seoul, South Korea. As one of the oldest medical schools in South Korea, it has been historically regarded as one of the country's top medical schools. The school was founded as Chosun Women's Medical Training Institute in 1928 by Rosetta Sherwood Hall. The institute was subsequently renamed several times and ultimately merged with Korea University to become Korea University College of Medicine. So far, the school has produced over 7,000 graduates, most of whom are working as prominent physicians and public health advocates worldwide.
Website: https://medicine.korea.ac.kr/en/index.do
About the authors
Dr. Jason K. Sa is an Associate Professor in the Department of Biomedical Informatics at Korea University College of Medicine. He received his bachelor’s from the University of California Santa Barbara, and Ph.D. in Cancer Genomics from Sungkyunkwan University, followed by postdoctoral training at Samsung Medical Center. His research group focuses on uncovering key driver mechanisms of tumor evolutionary trajectories and biological processes to treatment response, to advance precision oncology. Professor Sa has published more than 70 peer-reviewed papers, including leading journals such as Nature Genetics, Cancer Cell, and Cancer Discovery.
Ms. Ji Yoon Lee received her B.S. from Korea University and is currently pursuing an integrated M.S.-Ph.D. degree in the Department of Biomedical Sciences at Korea University. Her prior research investigated the molecular characteristics of breast cancer patients across different age groups and ethnic backgrounds. More recently, her work focused on delineating the developmental trajectories of anaplastic meningioma through single-cell analysis, with an emphasis on characterizing tumor cell states and the surrounding microenvironment to identify actionable biomarkers.
END