Outer Radial Glia–Like Cells May Promote Glioblastoma Invasiveness

The persistence of glioma stem cells (GSC) is thought to be a major factor accounting for the treatment resistance of glioblastoma. Using single-cell RNA sequencing of 11 glioblastomas, Bhaduri, Di Lullo, and colleagues generated an atlas of the cell types found in these tumors. This confirmed the presence of several cell populations previously established to be present in glioblastoma, such as oligodendrocyte-precursor cells, microglia, tumor-associated macrophages, and dividing tumor cells, as well as populations of neurons (some of which expressed progenitor markers or cell-cycle genes), radial glia, and glial cells of variable maturity. Interestingly, each of the 11 tumors exhibited a unique combination of cell types and states, highlighting glioblastoma's intertumoral heterogeneity. An analysis of genes commonly used as GSC markers revealed that all 21 cell types identified expressed at least one gene associated with GSCs and stemness; however, the precise makeup of the stemness-marker genes expressed by these cells varied from tumor to tumor. Further investigation implied an enrichment of progenitor cell types among tumor cells and suggested that radial glia–like glioblastoma cells may be among the progenitor cells that propagate the tumors. Additional experiments showed that reexpression of genes involved in the development of outer radial glial cells (oRG; cells normally found in the developing human brain) in GSCs had effects similar to those seen during oRG development, such as mitotic somal translocation (MST), which may allow these cells to participate in glioblastoma expansion and invasion into healthy brain tissue. Work with cortical organoids showed that injection with primary GSCs expressing a specific oRG-associated cell-surface marker (PTPRZ1) led to the development of tumors composed of diverse cell types resembling those observed in the original tumor. In mice, injection of PTPRZ1-positive oRGs increased glioblastoma invasiveness, a process found to be promoted by MST. Because MST is not believed to occur outside development in healthy contexts, targeting MST may be a viable treatment strategy for glioblastoma.

Bhaduri A, Di Lullo E, Jung D, Müller S, Crouch EE, Espinosa CS, Ozawa T, et al. Outer radial glia-like cancer stem cells contribute to heterogeneity of glioblastoma. Cell Stem Cell 2020;26:48–63.E6.

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