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

Michal Kostas1, Else Munthe1, Ellen Margrethe Haugsten1

  • 1Department 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.

Cell Reports
|June 5, 2026
PubMed

Insights

Inorganic phosphate (Pi) activates Fibroblast Growth Factor Receptor 1 (FGFR1) in osteosarcoma by entering mitochondria, increasing hydrogen peroxide, and oxidizing the receptor. This unveils a novel oncogenic mechanism and phosphate sensing pathway.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Signaling

Background:

  • Fibroblast Growth Factor Receptors (FGFRs) are key signaling proteins implicated in various cancers, including osteosarcoma (OS).
  • FGFR1's role in inorganic phosphate (Pi) sensing in osteoblasts is known, but the activation mechanism by Pi is unclear.
  • Osteosarcoma progression is linked to FGFR1 signaling, necessitating a deeper understanding of its activation pathways.

Purpose of the Study:

  • To elucidate the unconventional mechanism by which inorganic phosphate (Pi) activates Fibroblast Growth Factor Receptor 1 (FGFR1).
  • To investigate the dependence of osteosarcoma cell lines on FGFR1 and the role of Pi as an activating stimulus.
  • To explore the association between blood Pi levels, tumor growth, and FGFR1 activation in vivo.

Main Methods:

  • Assessed the dependence of osteosarcoma cell lines on FGFR1 for growth, with Pi as a potential activator.
  • Conducted in vivo experiments to correlate blood Pi levels with tumor growth.
  • Investigated the role of mitochondrial Pi transport and hydrogen peroxide (H2O2) production in FGFR1 activation.

Main Results:

  • A significant subset of osteosarcoma cell lines showed dependence on FGFR1 for growth, stimulated by Pi.
  • In vivo studies demonstrated a correlation between elevated blood Pi levels and osteosarcoma tumor growth.
  • Elevated Pi induces FGFR1 activation through mitochondrial Pi transport, leading to increased H2O2 production, which oxidizes key residues in FGFR1, promoting signaling.

Conclusions:

  • Identified a novel mechanism of FGFR1 activation by inorganic phosphate via mitochondrial pathways and oxidative stress.
  • Demonstrated that Pi-induced FGFR1 activation is a targetable oncogenic mechanism in osteosarcoma.
  • Provided an explanation for the physiological mechanism of Pi sensing by osteoblasts.
Keywords:
CP: cancerCP: molecular biologyFGFRFGFR1hydrogen peroxideinorganic phosphate (Pi)mitochondriaosteosarcomaoxidation

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