Selective calcium sensitivity in immature glioma cancer stem cells

Shimei Wee, Maria Niklasson, Voichita Dana Marinescu, Anna Segerman, Linnéa Schmidt, Annika Hermansson, Peter Dirks, Karin Forsberg-Nilsson, Bengt Westermark, Lene Uhrbom, Sten Linnarsson, Sven Nelander, Michael Andäng, Alfredo Quinones-Hinojosa

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere115698
JournalPloS one
Volume9
Issue number12
DOIs
StatePublished - Dec 22 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Wee, S., Niklasson, M., Marinescu, V. D., Segerman, A., Schmidt, L., Hermansson, A., Dirks, P., Forsberg-Nilsson, K., Westermark, B., Uhrbom, L., Linnarsson, S., Nelander, S., Andäng, M., & Quinones-Hinojosa, A. (2014). Selective calcium sensitivity in immature glioma cancer stem cells. PloS one, 9(12), [e115698]. https://doi.org/10.1371/journal.pone.0115698