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KAIST, 고려대학교 의과대학

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Mol. Cancer, Mar 04 2025, 24 (1) | https://doi.org/10.1186/s12943-025-02273-2 Distant origin of glioblastoma recurrence: neural stem cells in the subventricular zone serve as a source of tumor reconstruction after primary resection

Xue Li ^1,2,3,4†, Hyun Jung Kim ^5,6†, Jihwan Yoo ⁷, Yeonhee Lee ⁶, Chang Hyun Nam ⁵, Jonghan Park ², Soon-Tae Lee ⁸, TaeMin Kim ^2,9, Seung Hong Choi ¹⁰, Jae-Kyung Won¹¹, Sung-Hye Park ¹¹, Young Seok Ju⁵, Jong Bae Park ¹², Se Hoon Kim ¹³, Jong Hee Chang ¹⁴, Hong-Gyun Wu ^1,2,3, Chul-Kee Park^15,16, Jeong Ho Lee ^5,17*, Seok-Gu Kang ^14,18* and Joo Ho Lee ^1,2,3,*

¹Department of Radiation Oncology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
²Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
³Institute of Radiation Medicine, Medical Research Center, Seoul National University College of Medicine, Seoul, South Korea
⁴Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, People’s Republic of China
⁵Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, South Korea
⁶Department of Anatomy, Korea University College of Medicine, Seoul, South Korea
⁷Department of Neurosurgery, Brain Tumor Center, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
⁸Department of Neurology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
⁹Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
¹⁰Department of Radiology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
¹¹Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
¹²Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Goyang-si, Korea
¹³Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
¹⁴Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
¹⁵Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, South Korea
¹⁶Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, South Korea
¹⁷Sovargen Inc, Daejeon, South Korea
¹⁸Department of Medical Sciences, Yonsei University Graduate School, Seoul, South Korea

^†Xue Li and Hyun Jung Kim contributed equally to this work.

^*Corresponding authors: correspondence to Jeong Ho Lee, Seok-Gu Kang or Joo Ho Lee

Abstract

Glioblastoma (GBM) is the most aggressive and common type of primary malignant brain cancer in adults. GBM often recurs locally near the resection cavity (RC) following the surgical removal of primary tumors. Recent research has reported that neural stem cells (NSCs) in the subventricular zone (SVZ) harboring cancer-driving mutations serve as the cells of origin for human GBM. However, the pathological role of tumor-initiating NSCs in the SVZ in tumor recurrence remains to be elucidated. Here, we explore the potential contribution of mutation-harboring NSCs in the SVZ to tumor recurrence around the RC following surgical resection. Our hypothesis emerged from performing deep sequencing of longitudinal tissues from 10 patients with GBM, including (i) tumor-free SVZ tissue, (ii) primary tumor tissue, (iii) recurrent tumor tissue, and (iv) blood. As a result of this sequencing, we observed evidence suggesting that recurrent tumors show genetic links to the SVZ in 60% (6/10) of patients, which are distinct from the primary tumors. Using a genome-edited mouse model, we further identified that mutation-harboring NSCs appeared to migrate to the RC through the aberrant growth of oligodendrocyte progenitor cells, potentially contributing to the reconstruction of high-grade malignant gliomas in the RC. This process was associated with the CXCR4/CXCL12 axis, as supported by RNA sequencing data from human recurrent GBM. Taken together, our findings suggest that NSCs in human SVZ tissue may play a role in GBM recurrence, potentially highlighting a novel distant contributor of recurrence.

논문정보

형식Research article
게재일2025년 03월 (BRIC 등록일 2025-03-05)
연구진국내 연구진
분야 의약학 > 종양의학

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