Purinergic signaling promotes gliomagenesis through nuclear calcium transients

Intracellular Ca²⁺ 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 Ca²⁺ transients that promote tumor growth through unclear mechanisms. Using patient-derived GBM models, we show that these transients depend primarily on intracellular Ca²⁺ 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 Ca²⁺ transients via activation of metabotropic purinergic P2RY1 receptors, whose knockdown attenuates tumorigenicity in vitro and in vivo. Mechanistically, Ca²⁺ transients promote tumorigenesis via the nuclear Ca²⁺/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.