title: Ion channel expression patterns in glioblastoma stem cells with functional and therapeutic implications for malignancy.
abstract: Ion channels and transporters have increasingly recognized roles in cancer progression through the regulation of cell proliferation, migration, and death. Glioblastoma stem-like cells (GSCs) are a source of tumor formation and recurrence in glioblastoma multiforme, a highly aggressive brain cancer, suggesting that ion channel expression may be perturbed in this population. However, little is known about the expression and functional relevance of ion channels that may contribute to GSC malignancy. Using RNA sequencing, we assessed the enrichment of ion channels in GSC isolates and non-tumor neural cell types. We identified a unique set of GSC-enriched ion channels using differential expression analysis that is also associated with distinct gene mutation signatures. In support of potential clinical relevance, expression of selected GSC-enriched ion channels evaluated in human glioblastoma databases of The Cancer Genome Atlas and Ivy Glioblastoma Atlas Project correlated with patient survival times. Finally, genetic knockdown as well as pharmacological inhibition of individual or classes of GSC-enriched ion channels constrained growth of GSCs compared to normal neural stem cells. This first-in-kind global examination characterizes ion channels enriched in GSCs and explores their potential clinical relevance to glioblastoma molecular subtypes, gene mutations, survival outcomes, regional tumor expression, and experimental responses to loss-of-function. Together, the data support the potential biological and therapeutic impact of ion channels on GSC malignancy and provide strong rationale for further examination of their mechanistic and therapeutic importance.
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: Pollak
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.
authors.forename: Karan G
authors.initials: KG
authors.lastname: Rai
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Cory C
authors.initials: CC
authors.lastname: Funk
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Sonali
authors.initials: S
authors.lastname: Arora
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Eunjee
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Department of Hematology and Medical Oncology, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Institute for Systems Biology, Seattle, Washington, United States of America.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Price
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Paddison
authors.affiliation: Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington, United States of America.|Department of Neurosurgery, University of Washington, Seattle, Washington, United States of America.
authors.forename: Jan-Marino
authors.initials: JM
authors.lastname: Ramirez
authors.affiliation: Department of Neurosurgery, University of Washington, Seattle, Washington, United States of America.|Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, Washington, United States of America.|Houston Methodist Research Institute, Houston, Texas, United States of America.|Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas, United States of America.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Rostomily
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D006801:Humans; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D015398:Signal Transduction; D016019:Survival Analysis; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D007473:Ion Channels