Distant origin of glioblastoma recurrence: neural stem cells in the subventricular zone serve as a source of tumor reconstruction after primary resection

Xue Li, Hyun Jung Kim, Jihwan Yoo, Yeonhee Lee, Chang Hyun Nam, Jonghan Park, Soon-Tae Lee, Tae Min Kim, Seung Hong Choi, Jae-Kyung Won, Sung‑Hye Park, Young Seok Ju, Jong Bae Park, Se Hoon Kim, Jong Hee Chang, Hong-Gyun Wu, Chul-Kee Park, Jeong Ho Lee, Seok-Gu Kang & Joo Ho Lee

Molecular Cancer volume 24, Article number: 64 (2025)

Abstract (원문 요약)

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.

국문 초록 요약

 교모세포종(GBM)은 매우 공격적이며 성인에서 가장 흔한 악성 뇌종양이지만, 수술·방사선·TMZ 치료에도 불구하고 거의 항상 재발한다. 기존에는 재발이 수술 후 남은 잔존 종양세포의 증식 때문이라고 여겨졌지만, 본 연구는 뇌실하영역(SVZ)의 돌연변이를 가진 신경줄기세포(NSCs)가 수술부위 주변(RC) 에 새로운 종양을 다시 형성하는 재발 기원일 수 있음을 제시한다.

10명의 환자에서 SVZ–초기 종양–재발 종양의 유전체 연속성을 분석한 결과, 재발 종양의 60%가 기존 종양과 다른 진화 경로를 갖고 있으며, SVZ 변이 세포와 더 밀접한 유전적 연관성을 보였다.

동물 모델에서도 이와 동일하게, SVZ 변이 세포가 수술로 인해 손상된 뇌 환경 신호(CXCR4–CXCL12 축)에 의해 RC로 이동해 종양을 다시 만들었다.또한 CXCR4 억제제(AMD3100)를 사용한 결과, SVZ 세포 이동 및 종양 재형성이 억제되고 생존기간이 연장되었다.

이 연구는 GBM 재발이 단순히 남은 종양세포 때문이 아니라, SVZ에 존재하는 암-기원성 줄기세포가 수술 후 환경 변화에 반응하여 재형성된 결과일 수 있으며, CXCR4 경로가 GBM 재발 억제를 위한 치료 타깃이 될 수 있음을 시사한다.

연구 필요성

• GBM 재발 메커니즘에 새로운 생물학적 기원(SVZ-derived recurrence) 가능성이 존재하지만,

• 이를 증명하기 위한 환자 샘플 기반 유전체 분석 + 시간축 기반 동물 모델 연구가 부족했다.

• 만약 재발 종양의 주요 발원지가 잔존 종양이 아닌 SVZ NSCs라면,기존 치료 전략(잔존 종양 표적 중심)만으로는 재발을 차단할 수 없으며,전혀 다른 치료 타깃(CXCR4 경로, SVZ niche modulation)이 필요하다.

  

  [Evidence of SVZ NSC involvement in glioblastoma recurrence with cancer-driving mutations.]

  주요 실험 방법

연구 단계	실험 종류	목적
① 환자 샘플 정밀 유전체 분석	WGS + Deep sequencing	SVZ–재발 종양 연결성 확인
② CRISPR 마우스 제작	NSC-specific editing	SVZ 변이 세포 모델링
③ 종양 형성 & 절제 모델	Orthotopic transplantation + surgery	임상 재발 상황 재현
④ 세포 이동 분석	형광 lineage tracing	재발 종양 기원 규명
⑤ 기전 규명	RNA-seq	CXCR4 signaling 규명
⑥ 기능 검증	AMD3100 처리	CXCR4의 필요성 검증
⑦ in vitro 분석	NSC 분화 assay	세포 운명 결정 매커니즘 확인

주요 실험 결과

(1) 환자 분석 결과 — SVZ가 재발 종양의 클론과 연결됨

• 6/10 환자(60%)에서

  
  

  primary tumor와 recurrent tumor는 서로 유전적 연결성이 없지만, recurrent tumor는 SVZ 조직과 동일 돌연변이를 공유.

• 이는 재발 종양이 residual tumor가 아닌 SVZ mutation-bearing NSCs에서 기원했음을 의미.

  
  
  
  

 (2) 동물 모델 결과 — 재발 종양의 절반 이상이 SVZ에서 유래

• 수술 이후 재발된 종양의 기원 분석 결과:

재발 종양 기원	비율
SVZ-derived cells (GFP+)	약 54%
residual tumor re-growth (tdTomato+)	약 31%
혼합형	약 15%

(재발의 주된 기원이 SVZ mutation-harboring NSCs임을 직접 입증)

(3) 재발 과정 — SVZ 변이 세포가 수술 부위로 이동 → OPC로 분화 → 종양 재건

• SVZ NSCs는 수술 직후 생성되는 손상 신호(cytokine environment) 를 따라 이동하며,

• Olig2+/PDGFRα+ OPC lineage 로 분화하여 재발 종양을 재구성함.

  
  
  
  

 (4) 기전 — CXCL12–CXCR4 chemotaxis signaling이 핵심

• RNA-seq 분석에서 수술 후 RC 주변 혈관이 CXCL12 분비 증가

• 이동하는 SVZ 세포는 CXCR4 고발현

• → “CXCL12 gradient → CXCR4-driven migration”

  
  
  
  

임상 샘플에서도:

• RC에서 재발한 환자(Local recurrence) 는 CXCR4 발현이 높았으며, 생존율이 더 나쁨(p=0.018).

  
  
  
  

 (5) 기능 억제 실험 — CXCR4 억제제 투여 시 재발 억제

• CXCR4 inhibitor AMD3100 투여 결과:

  • SVZ 세포 이동 감소

  • OPC 분화 차단

  • 재발 종양 생성 억제

  • 생존율 개선

이는 CXCR4 pathway가 치료 표적(targetable mechanism) 임을 보여준다.

결론

·                   교모세포종 재발은 단순한 잔존 종양 확장이 아니라,

·                   SVZ에 남아있는 돌연변이 신경줄기세포가 손상 환경에 반응해 재발 종양을 형성하는 과정일 수 있다.

·                   특히 CXCR4–CXCL12 신호축은 이 이동·재형성 과정의 핵심이며,CXCR4 억제는 재발 예방 전략으로 유망하다.

연구 한계

한계	문제점	필요한 후속 연구
작은 샘플 수	대표성 부족	multi-center 확장 연구
단일 시점 분석	진화 과정 추적 불가	longitudinal sampling / liquid biopsy
재발 기원 다양성	SVZ 단독 기원 아님	subtype biomarker validation
동물 모델 단순화	실제 환자 생물학 반영 한계	PDX, organoid + immune-competent 모델
CXCR4 pathway 특이성 부족	injury response confounding	pathway hierarchy mapping
AMD3100 translation gap	임상 적용성 미확립	약동학/병용요법 임상시험