Cell-of-origin susceptibility to glioblastoma formation declines with neural lineage restriction. Nat Neurosci 2019 Apr;22(4):545-555
Date
02/20/2019Pubmed ID
30778149Pubmed Central ID
PMC6594191DOI
10.1038/s41593-018-0333-8Scopus ID
2-s2.0-85061730449 (requires institutional sign-in at Scopus site) 88 CitationsAbstract
The contribution of lineage identity and differentiation state to malignant transformation is controversial. We have previously shown that adult neural stem and early progenitor cells give origin to glioblastoma. Here we systematically assessed the tumor-initiating potential of adult neural populations at various stages of lineage progression. Cell type-specific tamoxifen-inducible Cre recombinase transgenes were used to target glioblastoma-relevant tumor suppressors Nf1, Trp53 and Pten in late-stage neuronal progenitors, neuroblasts and differentiated neurons. Mutant mice showed cellular and molecular defects demonstrating the impact of tumor suppressor loss, with mutant neurons being the most resistant to early changes associated with tumor development. However, we observed no evidence of glioma formation. These studies show that increasing lineage restriction is accompanied by decreasing susceptibility to malignant transformation, indicating a glioblastoma cell-of-origin hierarchy in which stem cells sit at the apex and differentiated cell types are least susceptible to tumorigenesis.
Author List
Alcantara Llaguno S, Sun D, Pedraza AM, Vera E, Wang Z, Burns DK, Parada LFAuthor
Daochun Sun PhD Assistant Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain Neoplasms
Cell Lineage
Cell Proliferation
Female
Glioblastoma
Male
Mice, Transgenic
Neural Stem Cells
Neurofibromin 1
Neurons
PTEN Phosphohydrolase
Tumor Suppressor Protein p53
Tumor Suppressor Proteins
