In vivo functional genomics identifies essentiality of potassium homeostasis in medulloblastoma

Distinguishing tumor maintenance genes from initiation, progression, and passenger genes is fundamental for developing effective cancer therapy. We engineered a Lazy Piggy screening system to first dysregulate and later restore gene expression using the Sleeping Beauty/piggyBac hybrid transposon. In vivo Lazy Piggy insertion and remobilization deplete insertions non-essential for tumor survival while enriching for maintenance insertions, uncovering potassium channels in the maintenance of medulloblastoma, the most common pediatric brain malignancy. KCNB2 is the most overexpressed potassium channel in human medulloblastoma, and Kcnb2 knockout in mice diminishes the replicative potential of medulloblastoma-propagating cells to mitigate tumor growth. Mechanistically, Kcnb2 governs potassium homeostasis to regulate plasma membrane tension-gated EGFR signaling, which drives the proliferative expansion of medulloblastoma-propagating cells. Collectively, our Lazy Piggy functional genomics reveals potassium homeostasis as a tumor maintenance essentiality and elucidates a mechanism by which potassium homeostasis integrates biomechanical and biochemical signaling to promote medulloblastoma aggression. ### Competing Interest Statement The authors have declared no competing interest.