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

Area of Science:

• Neuro-oncology
• Cancer Stem Cell Biology
• Glioma Research

Background:

• Diffuse invasion is a major challenge in treating pediatric high-grade glioma (pHGG), leading to treatment failure.
• Identifying the cellular mechanisms driving pHGG invasion is crucial for developing effective anti-invasion therapies.

Purpose of the Study:

• To identify cellular drivers of diffuse invasion in pediatric high-grade glioma (pHGG).
• To investigate the role of CD133 and CD57 markers in glioma stem cells (CSCs) and their invasive potential.

Main Methods:

• Isolation of invasive (HGG ^INV) and tumor core (HGG ^TC) cell pairs from ten highly invasive patient-derived orthotopic xenograft (PDOX) models of pHGG.
• Cancer stem cell (CSC) profiling using CD133 and CD57 markers to analyze cell populations at the invasive front.
• Assessment of self-renewal capacities and invasive potential of different CSC subpopulations through direct implantation and cell depletion experiments in mouse brains.

Main Results:

• pHGG ^INV cells exhibited intrinsically higher invasiveness compared to their matching pHGG ^TC counterparts.
• CD57⁺CD133^- cells were identified as the most abundant CSCs at the invasive front, displaying the highest self-renewal capacity, mediated by NANOG and SHH.
• Direct implantation of CD57⁺ cells (CD57⁺/CD133^- and CD57⁺/CD133⁺) led to diffuse invasion, while depletion of CD57⁺ cells abrogated invasion.

Conclusions:

• CD57 is confirmed as a novel marker for glioma stem cells.
• CD57⁺CD133^- and CD57⁺CD133⁺ cells are identified as key cellular drivers of pHGG invasion.
• A new dual-mode hierarchy of HGG stem cells is proposed, highlighting the significance of CD57 expression in invasion.