Molecular profiling uncovers KCa2.3 as key driver of pacemaker cells in glioblastoma

AI Summary

Distinct transcriptional programme identifies highly Ca2+ active glioblastoma cells, including upregulated cholesterol biosynthesis, TM-network markers, KCa1.1 and KCa2.3.
In silico modelling nominated KCa2.3 as uniquely compatible with pacemaker electrophysiology and showed increased KCa2.3 expression in pacemaker cells.
Genetic and pharmacological KCa2.3 inhibition disrupted pacemaker function, reduced network Ca2+ activity, and edelfosine lowered tumour burden in human brain spheroids.

TL;DR (AI Generated)

RESULTS: We identified a distinct transcriptional program that captures highly Ca2+ active glioblastoma cells, including pacemaker cells, across preclinical models and human glioblastoma specimens.

Consistently, KCa2.3 expression was increased in pacemaker cells, and both genetic and pharmacological perturbation of KCa2.3 selectively disrupted pacemaker function, resulting in reduced network-wide Ca2+ activity.

CONCLUSIONS: We present the first experimental approach to characterize molecular factors of glioblastoma pacemaker cells in a broad and unbiased manner, and identify KCa2.3 as a novel pacemaker gene and promising therapeutic target.

Basic summary

Neuro Oncol. 2026 Nov 10:noag278. doi: 10.1093/neuonc/noag278. Online ahead of print.

ABSTRACT

BACKGROUND: Glioblastoma is orchestrated by pacemaker cancer cells, a rare population preferentially residing at the hubs of tumor cell networks. These cells autonomously generate periodic Ca2+ oscillations that drive glioblastoma network function, resilience, and disease progression. To date, the Ca2+-activated K+ channel KCa3.1 is the only known driver of pacemaker function, calling for studies to identify additional factors – to better understand a key component of glioblastoma pathobiology, and uncover novel therapeutic targets.

METHODS: A molecular Ca2+ integrator technology enabled the transcriptional profiling of highly Ca2+-active glioblastoma cells, a population enriched for pacemaker cells. Putative regulators of pacemaker function were interrogated using genetic, pharmacological, and computational approaches across complementary glioblastoma models.

RESULTS: We identified a distinct transcriptional program that captures highly Ca2+ active glioblastoma cells, including pacemaker cells, across preclinical models and human glioblastoma specimens. This program comprised upregulated cholesterol biosynthesis enzymes, TM-network markers (Aquaporin-4 and Cystatin C), and the Ca2+-activated K+ channels KCa1.1 and KCa2.3. Amongst these components, in silico modeling identified KCa2.3 as the only channel compatible with executing pacemaker function. Consistently, KCa2.3 expression was increased in pacemaker cells, and both genetic and pharmacological perturbation of KCa2.3 selectively disrupted pacemaker function, resulting in reduced network-wide Ca2+ activity. Ultimately, pharmacological inhibition of KCa2.3 with edelfosine reduced tumor burden in human brain spheroids.

PMID:43006914 | DOI:10.1093/neuonc/noag278

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