You are here

| Neural Stem Cells

Subventricular Zone Neural Stem Cells Identified as Cell of Origin for Glioblastoma

Comment

Discuss

Review of “Human glioblastoma arises from subventricular zone cells with low-level driver mutations” from Nature by Stuart P. Atkinson 

Studies have suggested that self-renewing and proliferative neural stem cells (NSCs) present in the human subventricular zone (SVZ) may represent the cell-of-origin for the devastating and currently incurable brain tumor glioblastoma multiforme (GBM) [1-3]. As we currently lack evidence for the involvement of NSCs in human patients, researchers from the laboratories of Seok-Gu Kang (Yonsei University College of Medicine, Seoul) and Jeong Ho Lee (Korea Advanced Institute of Science and Technology, Daejeon, South Korea) examined somatic mutations in normal SVZ and matched tumor tissue and genome-edited mouse models.

Reporting in Nature, Lee et al. now provide evidence that astrocyte-like NSCs in the SVZ contain driver mutations of GBM and therefore represent the cell of origin for this incurable brain tumor, a finding that may encourage the development of novel therapeutic strategies [4].

Initial deep sequencing analysis of tissues derived from patients with GBM [5] discovered that over 50% of patients contained low-level GBM driver mutations in normal SVZ tissue (away from the tumor), with the GBM tumor expressing high levels of GBM driver mutations. Interestingly, the study highlighted the importance of TERT promoter mutations encountered at low levels in all of the tumor-free SVZ specimens harboring driver mutations; this may represent an early and common event through which NSCs in the SVZ avoid replicative senescence, thereby providing a greater chance of acquiring GBM driver mutations over time [6].

To identify the exact SVZ cell population involved, the authors employed single-cell sequencing and laser microdissection both of patient brain tissue and tissues derived from a CRISPR/Cas9-mediated genome editing mouse model of GBM. From these assays, they established that NSCs from the astrocytic ribbon of the SVZ carried the driver mutations, migrated away from the SVZ, and eventually generated high-grade malignant gliomas in distant brain regions.

The authors are confident that the results of their new study firmly identify astrocyte-like NSCs from the SVZ as the cell-of-origin for GBM and that this information will aid the development of new treatment strategies aimed at both GBM and other human brain disorders that may be foster by low-level somatic mutations [7].

For more on the importance of SVZ-NSCs in cancer and brain disorders, stay tuned to the Stem Cells Portal!

References

  1. Sanai N, Tramontin AD, Quinones-Hinojosa A, et al., Unique astrocyte ribbon in adult human brain contains neural stem cells but lacks chain migration. Nature 2004;427:740-4.
  2. Alcantara Llaguno S, Chen J, Kwon CH, et al., Malignant astrocytomas originate from neural stem/progenitor cells in a somatic tumor suppressor mouse model. Cancer Cell 2009;15:45-56.
  3. Tomasetti C, Li L, and Vogelstein B, Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 2017;355:1330-1334.
  4. Lee JH, Lee JE, Kahng JY, et al., Human glioblastoma arises from subventricular zone cells with low-level driver mutations. Nature 2018;560:243-247.
  5. Li YM, Suki D, Hess K, et al., The influence of maximum safe resection of glioblastoma on survival in 1229 patients: Can we do better than gross-total resection? J Neurosurg 2016;124:977-88.
  6. Bell RJ, Rube HT, Xavier-Magalhaes A, et al., Understanding TERT Promoter Mutations: A Common Path to Immortality. Mol Cancer Res 2016;14:315-23.
  7. Lee JH, Somatic mutations in disorders with disrupted brain connectivity. Exp Mol Med 2016;48:e239.