title: Selective calcium sensitivity in immature glioma cancer stem cells.
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 chemo- and radiation therapy posing a therapeutic challenge. To uncover stemness-associated 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 (NSC-proximal) 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.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Shimei
authors.initials: S
authors.lastname: Wee
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Maria
authors.initials: M
authors.lastname: Niklasson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Voichita Dana
authors.initials: VD
authors.lastname: Marinescu
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Segerman
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Linnéa
authors.initials: L
authors.lastname: Schmidt
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Hermansson
authors.affiliation: The Hospital for Sick Children, University of Toronto, Toronto, Canada.
authors.forename: Peter
authors.initials: P
authors.lastname: Dirks
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Forsberg-Nilsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Westermark
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Lene
authors.initials: L
authors.lastname: Uhrbom
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Sten
authors.initials: S
authors.lastname: Linnarsson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Andäng
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002118:Calcium / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D002118:Calcium