Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma

Within high-grade gliomas, the precise identities and functional roles of stem-like cells remain unclear. In the normal neurogenic niche, ID (Inhibitor of DNA-binding) genes maintain self-renewal and multipotency of adult neural stem cells. Using PDGF- and KRAS-driven murine models of gliomagenesis, we show that high Id1 expression (Id1^high) identifies tumor cells with high self-renewal capacity, while low Id1 expression (Id1^low) identifies tumor cells with proliferative potential but limited self-renewal capacity. Surprisingly, Id1^low cells generate tumors more rapidly and with higher penetrance than Id1^high cells. Further, eliminating tumor cell self-renewal through deletion of Id1 has modest effects on animal survival, while knockdown of Olig2 within Id1^low cells has a significant survival benefit, underscoring the importance of non-self-renewing lineages in disease progression.