Bruno Constantin, « Calcium signaling in cancer stem cells »
On Wednesday, Nov. 17, during the “Ions channels & Cancer” session ».
Cancer stem cells are a subpopulation of tumor cells that proliferate, self-renew and produce various tumoral cells building-up the tumor. Responsible for the sustained growth of malignant tumors, cancer stem cells are proposed to play significant roles in cancer resistance to standard treatment and in tumor recurrence. Among the mechanisms that are dysregulated in neoplasms, those related to intracellular Ca2+ signaling play a significant role in various aspects of cancers. Ca2+ is a ubiquitous second messenger whose fluctuations of its intracellular concentrations are tightly controlled by membrane ion channels, pumps, exchangers and Ca2+ binding proteins. These components support the genesis of Ca2+ signals with specific spatio-temporal characteristics that define the cell response. Being involved in the coupling of extracellular events with intracellular responses, the Ca2+ toolkit is often hijacked by cancer cells to promote notably their proliferation and invasion. Growing evidence obtained during the last decade pointed to a role of Ca2+ handling and mishandling in cancer stem cells. This lecture is highlighting the complex roles of Ca2+ toolkit and signaling in cancer stem cells and shows that numbers of Ca2+ signaling actors promote cancer stem cell state and are associated with cell resistance to current cancer treatments. Part of our ongoing studies are directed towards identifying the function and regulation of store-operated calcium entry, the transient receptor potential channel, TRPC1, the calcium channel, Orai1, and the ER regulator of calcium channels, STIM1 in glioblastoma stem cells, and leukemic progenitors. We have provided evidence that expression of TRPC1 and STIM1 is dependent on Bcr-Abl oncogene and that Store-Operated Calcium Entry (SOCE), a downregulated influx in leukemic progenitors, is an essential component of the agonist-stimulated Ca2+ influx mechanism that is required for sustained NFAT nucleus translocation (Cabanas et al., 2018). We have also identified calcium entry as an important component of cell signaling controlling human glioblastoma stem cells activity. Inhibition of SOC dependent calcium entries decreases proliferation impairs self-renewal and reduces expression of pluripotency proteins of CSC from GBM (Terrier et al., 2021). Our data showing the ability of Store-Operated Calcium Channels (SOCC) inhibitors to impede CSC self-renewal pave the way for a strategy to target the cells considered as responsible for conveying GBM resistance to treatment and tumor relapse.