Journal of neuro-oncology · 2025
T-type calcium channels regulate medulloblastoma and can be targeted for therapy.
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Dube Collin J, Lai Michelle, Zhang Ying, Saha Shekhar, Yener Ulas, Hanif Farina, Hudson Kadie, Gibert Myron K, Marcinkiewicz Pawel, Sun Yunan, Vegiraju Tanvika, Xu Esther, Sorot Aditya, Gallagher Rosa I, Wulfkuhle Julia D, Vernon Ashley, Dell'Olio Lily, Anbu Rajitha, Mulcahy Elizabeth, Kefas Benjamin, Guessous Fadila, Petricoin Emanuel F, Abounader Roger
Аннотация
PURPOSE: The goal of this study was to investigate the role and therapeutic targeting of T-type calcium channels in medulloblastoma, a common and deadly pediatric brain tumor that arises in the cerebellum.
METHODS: T-type calcium channel expression was assessed in publicly available bulk and single cell RNA-seq datasets. The effects of T-type calcium channel blocker mibefradil on cell growth, death and invasion were assessed with cell counting, alamar blue, trypan blue and transwell assays. Proteomic-based drug target and signaling pathway mapping was performed with Reverse Phase Protein Arrays (RPPA). Co-expression modules of single cell RNA-seq data were generated using high dimensional weighted gene co-expression network analysis (hdWGCNA). Orthotopic xenografts were used for therapeutic studies with the T-Type calcium channel blocker mibefradil.
RESULTS: T-type calcium channels were upregulated in more than 30% of medulloblastoma tumors and patients with high expression associated with a worse prognosis. T-type calcium channels had variable expression across all the subgroups of medulloblastoma at the bulk RNA-seq and single-cell RNA-seq level. Mibefradil treatment or siRNA mediated silencing of T-type calcium channels inhibited tumor cell growth, viability and invasion. RPPA-based protein/phosphoprotein signal pathway activation mapping of T-type calcium channel inhibition and single cell hdWGCNA identified altered cancer signaling pathways. Oral administration of mibefradil inhibited medulloblastoma xenograft growth and prolonged animal survival.
CONCLUSION: Our results represent a first comprehensive multi-omic characterization of T-type calcium channels in medulloblastoma and provide preclinical data for repurposing mibefradil as a treatment strategy for these relatively common pediatric brain tumors.
METHODS: T-type calcium channel expression was assessed in publicly available bulk and single cell RNA-seq datasets. The effects of T-type calcium channel blocker mibefradil on cell growth, death and invasion were assessed with cell counting, alamar blue, trypan blue and transwell assays. Proteomic-based drug target and signaling pathway mapping was performed with Reverse Phase Protein Arrays (RPPA). Co-expression modules of single cell RNA-seq data were generated using high dimensional weighted gene co-expression network analysis (hdWGCNA). Orthotopic xenografts were used for therapeutic studies with the T-Type calcium channel blocker mibefradil.
RESULTS: T-type calcium channels were upregulated in more than 30% of medulloblastoma tumors and patients with high expression associated with a worse prognosis. T-type calcium channels had variable expression across all the subgroups of medulloblastoma at the bulk RNA-seq and single-cell RNA-seq level. Mibefradil treatment or siRNA mediated silencing of T-type calcium channels inhibited tumor cell growth, viability and invasion. RPPA-based protein/phosphoprotein signal pathway activation mapping of T-type calcium channel inhibition and single cell hdWGCNA identified altered cancer signaling pathways. Oral administration of mibefradil inhibited medulloblastoma xenograft growth and prolonged animal survival.
CONCLUSION: Our results represent a first comprehensive multi-omic characterization of T-type calcium channels in medulloblastoma and provide preclinical data for repurposing mibefradil as a treatment strategy for these relatively common pediatric brain tumors.