Selective calcium sensitivity in immature glioma cancer stem cells

Tumor-initiating cells are a subpopulation in aggressive cancers that exhibit traits shared with stem cells, including the ability to self-renew and differentiate, commonly referred to as stemness. In addition, such cells are resistant to chemoand radiation therapy posing a therapeutic challenge. To uncover stemnessassociated functions in glioma-initiating cells (GICs), transcriptome profiles were compared to neural stem cells (NSCs) and gene ontology analysis identified an enrichment of Ca²⁺ signaling genes in NSCs and the more stem-like (NSCproximal) GICs. Functional analysis in a set of different GIC lines regarding sensitivity to disturbed homeostasis using A23187 and Thapsigargin, revealed that NSC-proximal GICs were more sensitive, corroborating the transcriptome data. Furthermore, Ca²⁺ drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca²⁺ sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca²⁺. Conversely, a higher number of and higher expression levels of Ca²⁺ binding genes that may buffer Ca²⁺, were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca²⁺ sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca²⁺ drug sensitivity. The correlation between high expression of Ca²⁺ channels (such as GRIA1) and sensitivity to Ca²⁺ drugs was confirmed in an additional nine novel GIC lines. Calcium drug sensitivity also correlated with expression of the NSC markers nestin (NES) and FABP7 (BLBP, brain lipid-binding protein) in this extended analysis. In summary, NSC-associated NES⁺/FABP7⁺/GRIA1⁺ GICs were selectively sensitive to disturbances in Ca2+ homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells.