Unconventional activation of the proto-oncogene FGFR1 by extracellular phosphate via H2O2-mediated kinase oxidation

  • Cell Rep. 2026 Jun 23;45(6):117504. doi: 10.1016/j.celrep.2026.117504.
Michal Kostas  1 ,  Else Munthe  1 ,  Ellen Margrethe Haugsten  1 ,  Duarte Mateus  2 ,  Vigdis Sørensen  3 ,  Jon Kristen Laerdahl  4 ,  Patrycja Szybowska  1 ,  Antoni Wiedlocha  2 ,  Laurène Alicia Lecaudey  1 ,  Sigve Nakken  1 ,  Kay Oliver Schink  5 ,  Harald Stenmark  2 ,  Jørgen Wesche  6
Affiliations
  • 1. Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Center for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.
  • 2. Center for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
  • 3. Center for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
  • 4. Department of Microbiology, Oslo University Hospital, Oslo, Norway.
  • 5. Center for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
  • 6. Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Center for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. Electronic address: [email protected].
PMID: 42247296 DOI: 10.1016/j.celrep.2026.117504
Abstract

Fibroblast Growth Factor Receptors (FGFRs) are important cellular signaling mediators and are implicated in numerous cancers, including osteosarcoma (OS). Recent research shows that FGFR1 participates in inorganic phosphate (Pi) sensing in osteoblasts, but how Pi activates FGFR1 remains unresolved. Here, we identify this unconventional mechanism of FGFR1 activation. We demonstrate that a large subset of OS cell lines is dependent on FGFR1 for growth, with Pi acting as an activating stimulus. In vivo experiments reveal that blood Pi levels are associated with tumor growth, implicating Pi-induced FGFR1 activation in OS progression. Elevated Pi triggers FGFR1 activation via Pi transport across the plasma membrane into mitochondria, increasing H2O2 production. The H2O2 burst oxidizes critical cysteine and methionine residues in FGFR1, promoting receptor activation and downstream signaling. These results reveal a targetable oncogenic mechanism for FGFR1 activation and explain the physiological Pi sensing mechanism.

Keywords
CP: cancer; CP: molecular biology; FGFR; FGFR1; hydrogen peroxide; inorganic phosphate (Pi); mitochondria; osteosarcoma; oxidation.
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