Terrié E, Déliot N, Benzidane Y,  Harnois T, Cousin L, Bois P,  Oliver L, Arnault P, Valette F, Constantin B and Coronas V (2021)

Cancers 2021, 13, 3428. https://doi.org/10.3390/cancers13143428

Simple Summary: Glioblastoma is a high-grade primary brain tumor that contains a subpopulation
of cells called glioblastoma stem cells, which are responsible for tumor initiation, growth and
recurrence after treatment. Recent transcriptomic studies have highlighted that calcium pathways
predominate in glioblastoma stem cells. Calcium channels have the ability to transduce signals from
the microenvironment and are therefore ideally placed to control cellular behavior. Using multiple
approaches, we demonstrate in five different primary cultures, previously derived from surgical
specimens, that glioblastoma stem cells express store-operated channels (SOC) that support calcium
entry into these cells. Pharmacological inhibition of SOC dramatically reduces cell proliferation and
stem cell self-renewal in these cultures. By identifying SOC as a critical mechanism involved in the
maintenance of the stem cell population in glioblastoma, our study will contribute to the framework
for the identification of new therapies against this deadly tumor.

Abstract: Glioblastoma is the most frequent and deadly form of primary brain tumors. Despite
multimodal treatment, more than 90% of patients experience tumor recurrence. Glioblastoma
contains a small population of cells, called glioblastoma stem cells (GSC) that are highly resistant to
treatment and endowed with the ability to regenerate the tumor, which accounts for tumor recurrence.
Transcriptomic studies disclosed an enrichment of calcium (Ca2+) signaling transcripts in GSC. In
non-excitable cells, store-operated channels (SOC) represent a major route of Ca2+ influx. As SOC
regulate the self-renewal of adult neural stem cells that are possible cells of origin of GSC, we
analyzed the roles of SOC in cultures of GSC previously derived from five different glioblastoma
surgical specimens. Immunoblotting and immunocytochemistry experiments showed that GSC
express Orai1 and TRPC1, two core SOC proteins, along with their activator STIM1. Ca2+ imaging
demonstrated that SOC support Ca2+ entries in GSC. Pharmacological inhibition of SOC-dependent
Ca2+ entries decreased proliferation, impaired self-renewal, and reduced expression of the stem cell
marker SOX2 in GSC. Our data showing the ability of SOC inhibitors to impede GSC self-renewal
paves the way for a strategy to target the cells considered responsible for conveying resistance to
treatment and tumor relapse.