Abstract
Medulloblastoma (MB) is the most common malignant primary brain tumor in children. Despite improved clinical outcomes, children with MB often suffer from consequences of treatment such as surgery, chemotherapy and radiation. MB is currently classified into 4 distinct molecular subtypes based on genomic alterations, gene expression profiles, response to treatment and cell of origin; WNT, SHH, Group 3, and Group 4. This extensive heterogeneity has revealed a critical need for subtype-specific, functionally validated biomarkers and therapeutic strategies. Using an unbiased high throughput flow cytometry screen, we identified CD271/p75NTR as a candidate SHH stem/progenitor cell marker. Here, we explored the functional role of CD271 in SHH MB cell lines and primary cultures, using gain/loss of function studies and treatments with a CD271 inhibitor, γ-secretase inhibitor (GSI). This was followed by cellular assays to measure sphere-forming capacity, self-renewal, proliferation and differentiation. Immunohistochemical (IHC) staining for CD271 was also conducted in formalin fixed paraffin embedded (FFPE) patient samples to assess expression of CD271 across MB subtypes. CD271 levels were high in SHH MB samples with minimal to no staining in WNT, Group 3, and Group 4 MBs. Stable overexpression of CD271 resulted in increased tumorsphere size, whereas CD271 knockdown cells exhibited a reversal of this cellular phenotype. Similarly, treatment of UI226 SHH MB primary cells with GSI also resulted in a significant decrease in tumorsphere growth and self-renewal, providing an opportunity to exploit CD271 as a therapeutic target. As CD271 appears to be specific to SHH MB, this marker may serve as a potential diagnostic tool. Further characterization of CD271 signaling in SHH MB could ultimately lead to development of targeted therapies that will lessen the broad impact of current toxic treatments, and improve the quality of life for children who survive long- term.
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