Targeting N-cadherin through fibroblast growth factor receptor-4: distinct pathogenetic and therapeutic implications

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• Pituitary tumors involve molecular aberrations with limited therapeutic targets.
• Pituitary tumor-derived fibroblast growth factor receptor-4 (ptd-FGFR4) is an oncogenic cytoplasmic isoform.
• ptd-FGFR4 recapitulates human pituitary tumor morphology in mice.

Purpose of the Study:

• To investigate the therapeutic potential of targeting ptd-FGFR4 in pituitary tumors.
• To examine the impact of FGFR4 tyrosine kinase inhibition on tumor growth and invasiveness.
• To validate findings in preclinical models and primary human pituitary tumors.

Main Methods:

• Utilized transgenic mice and xenograft models expressing ptd-FGFR4.
• Administered FGFR-selective inhibitor PD173074 systemically.
• Assessed tumor volume, invasiveness, N-cadherin expression, and retinoblastoma protein phosphorylation.
• Employed small interfering RNA for N-cadherin down-regulation.
• Analyzed primary human pituitary tumors for ptd-FGFR4 and N-cadherin expression.

Main Results:

• PD173074 treatment reduced tumor volume and invasiveness in ptd-FGFR4 xenografts.
• Inhibition of ptd-FGFR4 restored membranous N-cadherin staining.
• Mutation of Y754F in ptd-FGFR4 abrogated PD173074's inhibitory effect.
• N-cadherin down-regulation promoted invasive growth.
• Loss of membranous N-cadherin correlated with cytoplasmic FGFR4 and invasiveness in human tumors.
• PD173074 treatment restored N-cadherin and dephosphorylated retinoblastoma protein in human pituitary tumor cells.

Conclusions:

• ptd-FGFR4 is a significant oncogene in pituitary tumorigenesis.
• Targeting FGFR4 tyrosine kinase activity with PD173074 is a potential therapeutic strategy.
• N-cadherin misexpression is pathologically significant and mediated by FGFR4 signaling.
• Restoration of N-cadherin function is a key outcome of FGFR4 inhibition.