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Quiescence status of glioblastoma stem-like cells involves remodelling of Ca 2+ signalling and mitochondrial shape
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Edité par CCSD ; Nature Publishing Group -
International audience. 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. Multiform glioblastoma (GBM) is the most aggressive brain tumours with very poor prognosis. Despite a combination of surgical resection, radiotherapy and temozolomide (TMZ)-based chemotherapy, more than 90% of the patients show recurrence and the mean survival period rarely exceeds 2 years 1. According to the cancer stem cell model, the GBM lethality is due to a small sub-population of tumour cells with stem-like properties, called Glioblastoma Stem-Like Cells (GSLCs). The GSLCs have been further characterized as slow-cycling or relatively quiescent cells 2 , identified in vivo in a mouse model of glioblastoma 3 and in human glioblastoma tumors 4. These quiescent GSLCs are highly resistant to TMZ treatment 5. Quiescence is a cell-cycle arrest state which differs from the one observed in differentiation or senescence by the fact that it is reversible. Transcriptional profiling data reveals that quiescent stem cells are characterized by a common gene signature with the down-regulation of genes associated with cell-cycle progression (i.e. CCNA2, CCNB1 and CCNE2) and the upregulation of genes classified as tumour suppressors, including the cyclin-dependent kinase inhibitor p21 (CDKN1A) and the G0/G1 switch gene 2 (G0S2) 6,7. These data also show that quiescence is a G 0 phase and not a prolonged G 1 phase 8. Furthermore, quiescence is actively regulated by signals provided by the stem cell microenvironment. In glioblastoma tumours, quiescent stem-like tumour cells are found close to necrotic tissues, in specific niches characterized by an hypoxic 4,5,9 and acidic microenviron-ment 10,11. The role of the microenvironment in the control of GSLCs quiescence is still poorly understood. Considering that quiescence represents a strategy for GSLCs to evade killing, it is of utmost importance to better characterize the quiescent GSLCs and to understand what governs the transition from a proliferative to a quiescence state. Here, we performed transcriptomic analysis using RNAseq to establish the RNA signatures of proliferative and quiescent GSLCs. We showed that genes involved in Ca 2+ signalling are modulated in GSLCs and we explored the causal role of Ca 2+ during this transition. Our data points out the reversible remodelling of mitochondrial morphology from tubular to donut shape, associated with an increased capacity of mitochon-dria to capture Ca 2+ and with the modification of the kinetics of Ca 2+ influx through SOC. The remodelling of
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