The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Gastric adenocarcinoma (GC) is a leading cause of cancer mortality with limited treatment options.
• Fibroblast Growth Factor Receptors (FGFRs) are implicated in cancer, with FGFR4 showing STAT3-dependent regulation in H. pylori-infected GC.
• Targeting FGFR4 presents a potential therapeutic avenue for GC.

Purpose of the Study:

• To identify factors modulating FGFR4 signaling in gastric cancer.
• To explore the regulatory mechanism of FGFR4 in GC.
• To investigate the therapeutic potential of targeting the LIF/LIFR/FGFR4 axis.

Main Methods:

• RNA-sequencing analysis of GC patient biopsies, patient-derived organoids (PDOs), and cancer cell lines.
• Investigated the role of leukemia inhibitory factor (LIF) and its receptor (LIFR) in FGFR4 regulation.
• Utilized a LIFR inhibitor (LIR-201) and FGFR4 inhibitors (roblitinib, siRNA) to assess pathway modulation.

Main Results:

• FGFR4 expression and function are regulated by LIF in a JAK1/STAT3-dependent manner.
• A direct correlation between LIFR and FGFR4 expression was observed in GC patient cohorts.
• LIFR inhibition abrogated STAT3 phosphorylation and LIF-induced oncogenic effects, with FGFR4 identified as a downstream target.
• FGFR4 inhibition also reduced STAT3 phosphorylation and abrogated LIF's oncogenic effects.
• LIR-201 treatment inhibited the oncogenic potential of FGF19, the physiological ligand for FGFR4.

Conclusions:

• A novel regulatory mechanism of FGFR4 by the LIF/LIFR pathway in GC was uncovered.
• LIF and FGF19 signaling converge on the regulation of oncogenic STAT3 in gastric cancer cells.
• These findings highlight the LIF/LIFR/FGFR4/STAT3 axis as a potential therapeutic target for GC.