CD57 defines a novel cancer stem cell that drive invasion of diffuse pediatric-type high grade gliomas.

BACKGROUND

Diffuse invasion remains a primary cause of treatment failure in pediatric high-grade glioma (pHGG). Identifying cellular driver(s) of pHGG invasion is needed for anti-invasion therapies.

METHODS

Ten highly invasive patient-derived orthotopic xenograft (PDOX) models of pHGG were subjected to isolation of matching pairs of invasive (HGG) and tumor core (HGG) cells.

RESULTS

pHGG cells were intrinsically more invasive than their matching pHGG cells. CSC profiling revealed co-positivity of CD133 and CD57 and identified CD57CD133 cells as the most abundant CSCs in the invasive front. In addition to discovering a new order of self-renewal capacities, i.e., CD57CD133 > CD57CD133 > CD57CD133 > CD57CD133 cells, we showed that CSC hierarchy was impacted by their spatial locations, and the highest self-renewal capacities were found in CD57CD133 cells in the HGG front (HGG/CD57CD133 cells) mediated by NANOG and SHH over-expression. Direct implantation of CD57 (CD57/CD133 and CD57/CD133) cells into mouse brains reconstituted diffusely invasion, while depleting CD57 cells (i.e., CD57CD133) abrogated pHGG invasion.

CONCLUSION

We revealed significantly increased invasive capacities in HGG cells, confirmed CD57 as a novel glioma stem cell marker, identified CD57CD133 and CD57CD133 cells as a new cellular driver of pHGG invasion and suggested a new dual-mode hierarchy of HGG stem cells.