期刊
NATURE NEUROSCIENCE
卷 22, 期 4, 页码 545-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-018-0333-8
关键词
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资金
- Children's Tumor Foundation Young Investigator Award
- National Institutes of Health (NIH) T32 Postdoctoral Training Grant [2T32CA124334-06]
- NIH R01 grant [CA131313-01A1]
- National Cancer Institute R35 grant [CA210100]
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.
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