Quiescence status of glioblastoma stem-like cells involves remodelling of Ca(2+) signalling and mitochondrial shape

Quiescence is a reversible cell-cycle arrest which allows cancer stem-like cells to evade killing following therapies. Here, we show that proliferating glioblastoma stem-like cells (GSLCs) can be induced and maintained in a quiescent state by lowering the extracellular pH. Through RNAseq analysis we identified Ca(2+) signalling genes differentially expressed between proliferating and quiescent GSLCs. Using the bioluminescent Ca(2+) reporter EGFP-aequorin we observed that the changes in Ca(2+) homeostasis occurring during the switch from proliferation to quiescence are controlled through store-operated channels (SOC) since inhibition of SOC drives proliferating GSLCs to quiescence. We showed that this switch is characterized by an increased capacity of GSLCs’ mitochondria to capture Ca(2+) and by a dramatic and reversible change of mitochondrial morphology from a tubular to a donut shape. Our data suggest that the remodelling of the Ca(2+) homeostasis and the reshaping of mitochondria might favours quiescent GSLCs’ survival and their aggressiveness in glioblastoma.