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(INV)) and tumor core (HGG(TC)) cells. RESULTS: pHGG(INV) cells were intrinsically more invasive than their matching pHGG(TC) cells. CSC profiling revealed co-positivity of CD133 and CD57 and identified CD57(+)CD133(-) cells as the most abundant CSCs in the invasive front. In addition to discovering a new order of self-renewal capacities, i.e., CD57(+)CD133(-) > CD57(+)CD133(+) > CD57(-)CD133(+) > CD57(-)CD133(-) cells, we showed that CSC hierarchy was impacted by their spatial locations, and the highest self-renewal capacities were found in CD57(+)CD133(-) cells in the HGG(INV) front (HGG(INV)/CD57(+)CD133(-) 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., CD57(-)CD133(+)) abrogated pHGG invasion. CONCLUSION: We revealed significantly increased invasive capacities in HGG(INV) cells, confirmed CD57 as a novel glioma stem cell marker, identified CD57(+)CD133(-) and CD57(+)CD133(+) cells as a new cellular driver of pHGG invasion and suggested a new dual-mode hierarchy of HGG stem cells.