Language

English

Publication Date

6-9-2025

Journal

Developmental Cell

DOI

10.1016/j.devcel.2025.01.001

PMID

39862856

PMCID

PMC13162209

PubMedCentral® Posted Date

5-13-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is critical for developing effective therapies. We employed a functional genomic approach using the Lazy Piggy transposon to identify tumor maintenance genes in vivo, and applied this to SHH medulloblastoma (MB). Combining Lazy Piggy screening in mice and transcriptomic profiling of human MB, we identified the voltage-gated potassium channel KCNB2 as a candidate maintenance driver. KCNB2 governs cell volume of MB-propagating cells, with KCNB2 depletion causing osmotic swelling, decreased plasma membrane tension, and elevated endocytic internalization of EGFR, thereby mitigating proliferation of MB-propagating cells to ultimately impair MB growth. KCNB2 is largely dispensable for mouse development and KCNB2 knockout synergizes with anti-SHH therapy in treating MB. These results demonstrate the utility of the Lazy Piggy functional genomic approach in identifying cancer maintenance drivers, and elucidate a mechanism by which potassium homeostasis integrates biomechanical and biochemical signaling to promote MB aggression.

Keywords

Medulloblastoma, Animals, Mice, Hedgehog Proteins, Humans, Cerebellar Neoplasms, Shab Potassium Channels, Cell Proliferation, Mice, Knockout, Signal Transduction, Gene Expression Regulation, Neoplastic, ErbB Receptors

Published Open-Access

yes

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