Functional characterization and selective targeting of CD271+ cells in sonic hedgehog medulloblastoma
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Date
2019-01-14
Authors
Liang, Lisa
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Abstract
The extensive heterogeneity between and within medulloblastoma (MB) subgroups underscores a critical need for subtype-specific biomarkers and therapeutic strategies. Here, we employed a high throughput flow cytometry screening platform to identify CD271/p75NTR as a tumor propagating cell marker for SHH MB. In addition, we demonstrated the clinical utility of CD271 as a novel diagnostic marker using immunohistochemical (IHC) analysis and transcriptome profiling of MB patient samples. RNA sequencing analysis performed on CD271+ vs. CD271- SHH primary cultures revealed that these two subpopulations are molecularly distinct with CD271+ cells associated with an increase in cell survival, proliferation and migration. Importantly, we showed that MAPK signaling is upregulated in the CD271+ population, and treatment with MEK inhibitor selumetinib reduces endogenous CD271 levels, proliferation and migration in vitro. Selumetinib treatment in an intracerebellar xenograft mouse model also extended survival and reduced CD271 levels in vivo. Collectively, the data presented in this thesis demonstrate the utility of CD271 as a stem/progenitor marker, potential diagnostic and therapeutic target for SHH MB.
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Keywords
Medulloblastoma, CD271, Cancer stem cells