Abstract
Most patients with glioblastoma (GBM) die within 2 years. A major therapeutic goal is to target GBM stem cells (GSCs), a subpopulation of cells that contribute to treatment resistance and recurrence. Since their discovery in 2003, GSCs have been isolated using single-surface markers, such as CD15, CD44, CD133, and α6 integrin. It remains unknown how these single-surface marker–defined GSC populations compare with each other in terms of signaling and function and whether expression of different combinations of these markers is associated with different functional capacity. Using mass cytometry and fresh operating room specimens, we found 15 distinct GSC subpopulations in patients, and they differed in their MEK/ERK, WNT, and AKT pathway activation status. Once in culture, some subpopulations were lost and previously undetectable ones materialized. GSCs that highly expressed all 4 surface markers had the greatest self-renewal capacity, WNT inhibitor sensitivity, and in vivo tumorigenicity. This work highlights the potential signaling and phenotypic diversity of GSCs. Larger patient sample sizes and antibody panels are required to confirm these findings.
Highlights
Glioblastoma (GBM) is the most common and aggressive primary brain tumor
We obtained an average of 1.35 × 104 live cells per mg of tissue, and 3 × 106 viable cells were immediately labeled for mass cytometry
We found that the quadruple-high subpopulation, CD15hiCD44hiCD133hiα6 integrinhi, had high expression of pERK and non– phospho-β-catenin compared with cells with low expression of surface markers (Figure 3A)
Summary
Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Standard therapy includes surgery, radiation, temozolomide chemotherapy, and, more recently, tumor-treating fields [1]. GSCs tend to be enriched in serum-free media conditions, often referred to as stem cell media conditions. It remains unknown how GSC populations defined by single-surface markers compare with each other, in terms of intracellular signaling and function and whether expression of different combinations of these markers is associated with differences in the probability of tumor-forming capacity. It remains unknown whether all GSCs are alike or have their own hierarchy of function. These issues are important for how we study GBM in vitro and in animal models and understand intratumor and intertumor heterogeneity and treatment resistance
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