Scientists have discovered that normal-looking brain cells can acquire the first IDH mutation and quietly spread through the brain's cortex long before a tumor mass forms. This early, hidden phase may explain why the cancer is so difficult to eliminate and points to new possibilities for earlier detection and preventing recurrence.

Researchers Trace the Cancer Back to Normal Brain Cells

On January 9th, KAIST announced that a joint research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering and Professor Seok-Gu Kang of Yonsei University Severance Hospital identified the cellular origin of IDH-mutant glioma. The team found that these tumors arise from Glial Progenitor Cells (GPCs) that exist in normal brain tissue.

Glial Progenitor Cells (GPC): Cells that exist in the normal brain and can become the starting point for malignant brain tumors if genetic mutations occur.

To reach this conclusion, the researchers closely examined tumor samples collected during extensive surgical removal, along with nearby brain tissue that appeared healthy. They found that cells carrying the IDH mutation were already present in brain regions that looked completely normal to the naked eye.

Brain Tumors May Develop Slowly Over Time

These findings provide the first clear evidence that malignant brain tumors do not suddenly appear at a single moment. Instead, they can begin quietly within normal brain tissue and evolve gradually over many years before forming a detectable mass.

To confirm the identity of these early mutated cells, the team used "spatial transcriptomics" -- a cutting-edge analysis technology that shows "which genes are operating where" simultaneously. This approach confirmed that the mutation-bearing cells were Glial Progenitor Cells (GPCs) located in the cerebral cortex.

The researchers also recreated the process in animals. By introducing the same genetic "driver mutation" found in patients into the GPCs of mice, they successfully reproduced key steps of brain tumor development.

Different Brain Cancers Follow Different Paths

This study builds on earlier work by the same research group. In 2018, they reported that IDH wildtype glioblastoma, another aggressive brain cancer, originates from neural stem cells in the subventricular zone -- the source of new brain cells in the adult brain (Lee et al., Nature, 2018).

The new findings show that although IDH wildtype glioblastoma and IDH-mutant glioma are both malignant brain tumors, they arise from different types of cells and begin in different regions of the brain. This confirms that brain cancers can follow distinct biological paths depending on their subtype.

Implications for Early Diagnosis and Treatment

Professor Seok-Gu Kang (Co-Corresponding Author) explained the importance of this shift in understanding, stating, "Brain tumors may not start exactly where the tumor mass is visible. A target approach focused on the origin cells and the site of origin according to the brain tumor subtype will serve as a crucial clue to changing the paradigm of early diagnosis and recurrence suppression treatment."

Based on these results, Sovagen Co., Ltd, a faculty startup from KAIST, is developing a new RNA-based drug designed to slow or stop the progression and recurrence of IDH-mutant malignant brain tumors. At the same time, Severance Hospital is working on technologies to detect and control early mutant cells through the Korea-US Innovative Result Creation R&D project.

A Question That Started the Discovery

Dr. Jung Won Park (Postdoctoral Researcher at KAIST Graduate School of Medical Science and Engineering), a neurosurgeon and the study's sole first author, emphasized the collaboration behind the work. He said, "This achievement was made possible by combining KAIST's world-class basic science research capabilities with the clinical expertise of Yonsei Severance Hospital. The question I kept asking while treating patients -- 'Where does this tumor originate?' -- was the starting point of this research."

The findings were published on January 8th in the journal Science.

The research was supported by the Suh Kyung-bae Science Foundation, the National Research Foundation of Korea, the Ministry of Science and ICT, the Ministry of Health and Welfare, and the Korea Health Industry Development Institute (Physician-Scientist Training Program).