Purinergic signaling promotes gliomagenesis through nuclear calcium transients

  • bioRxiv. 2026 May 14:2026.05.11.724407. doi: 10.64898/2026.05.11.724407.
Shuai Wang  1 ,  Jenna Richter  1 ,  Claire D Kim  1 ,  Rebecca Ronnen  1 ,  Julia Cai  1 ,  Yunfei Song  1 ,  Sara Haddock  1 ,  Mark B Stoessel  2 ,  Hannah Dada  1 ,  Suzanne Gross  1 ,  Adler Guerrero  1 ,  Theodoris Karnavas  1 ,  Gabriele Stephan  1 ,  Greg Belizaire  1 ,  Luke Bonanni  1 ,  Danielle Golub  1 ,  Jonathan Sabio  1 ,  Hanna Schwarz  1 ,  Albert Jiang  1 ,  Nawshin Maleeha  1 ,  Anuva Ghosh  1 ,  Madelynn Yung  1 ,  Eric Grossman-Glover  1 ,  Jocelyn Tang  3 ,  Laura Gherghina  3 ,  Alex Donovan  3 ,  Andrea Leonard  1 ,  Luis Chiriboga  4 ,  Drew Jones  5 ,  Soomin C Song  4 ,  Esteban Mazzoni  3 ,  Theresa Vincent  6 ,  Robert J Schneider  6 ,  David Zagzag  1  4 ,  Yuki Miura  7 ,  Jayeeta Basu  2  8  9 ,  Andrea H Brand  2  3 ,  Dimitris G Placantonakis  1  2  3  10
Affiliations
  • 1. Department of Neurosurgery, NYU Grossman School of Medicine, New York, NY, USA.
  • 2. Neuroscience Institute, NYU Grossman School of Medicine, New York, NY, USA.
  • 3. Department of Cell Biology, NYU Grossman School of Medicine, New York, NY, USA.
  • 4. Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
  • 5. Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY, USA.
  • 6. Department of Microbiology, New York University Grossman School of Medicine, New York, NY, USA.
  • 7. Department of Molecular Pathobiology, NYU College of Dentistry, New York, NY, USA.
  • 8. Department of Psychiatry, NYU Grossman School of Medicine, New York, NY, USA.
  • 9. Center for Neural Science, New York University, New York, NY, USA.
  • 10. Perlmutter Cancer Center, NYU Langone Health, New York, NY, USA.
PMID: 42182450 DOI: 10.64898/2026.05.11.724407
Abstract

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.

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