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.
Highlights
Glioblastoma multiforme (GBM; grade IV glioma) is the most prevalent and malignant form of primary brain tumor in adults [1,2]
The strategy of comparing glioblastoma stemlike cells (GSCs) to neural stem cells (NSCs)/normal human astrocyte (NHA) was used as a first approximation to enrich for genes specific to malignant stem cell phenotypes and not shared by non-transformed neural progenitors or astrocytic glia
Using a Signal2Noise metric, which accounts for both mean absolute levels and variance within the classes, we found that 107 out of 266 ion channels highly contributed to the enrichment of ion channels in GSCs compared to control cells
Summary
Glioblastoma multiforme (GBM; grade IV glioma) is the most prevalent and malignant form of primary brain tumor in adults [1,2]. GBM tumors are especially difficult to treat, since surgical resection invariably leaves behind glioblastoma stemlike cells (GSCs), which are highly invasive tumor cells uniquely resistant to standard therapies. Several features of GSCs contribute to GBM malignancy following initial tumor formation, including rapid proliferation and highly diffuse invasion throughout the brain [5]. Standard chemotherapeutic agents, which eradicate the majority of GBM cells, have a reduced effect on GSCs, and surviving GSCs contribute to tumor recurrence, a hallmark of GBM [5,6]. These features underscore the necessity for development of novel therapeutic candidates that precisely target GSCs and halt uncontrolled growth and invasion.
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