Purinergic signaling promotes gliomagenesis through nuclear calcium transients

Abstract Intracellular Ca 2+ transients drive key developmental and physiological processes, yet their role in oncogenesis remains incompletely understood. In glioblastoma (GBM), an aggressive brain malignancy, tumor cellular networks exhibit self-sustaining Ca 2+ transients that promote tumor growth through unclear mechanisms. Using patient-derived GBM models, we show that these transients depend primarily on intracellular Ca 2+ stores and extend to the nucleus to drive tumorigenesis. A neuromodulator screen identified extracellular purines ATP and ADP as potent inducers of both nuclear and cytosolic Ca 2+ transients via activation of metabotropic purinergic P2RY1 receptors, whose knockdown attenuates tumorigenicity in vitro and in vivo . Mechanistically, Ca 2+ transients promote tumorigenesis via the nuclear Ca 2+ /calmodulin-dependent kinase CAMK4, which regulates transcriptional and epigenetic programs, as well as ribosomal DNA transcription. From the therapeutic perspective, pharmacologic P2RY1 inhibition suppresses tumor growth in vitro and in vivo . Collectively, these findings reveal a pharmacologically targetable oncogenic mechanism in GBM and possibly other malignancies.