Cancer-associated fibroblasts secrete FGF5 to inhibit ferroptosis to decrease cisplatin sensitivity in nasopharyngeal...

Area of Science:

• Oncology
• Cancer Biology
• Cellular Signaling

Background:

• Cisplatin (DDP)-based chemoradiotherapy is a standard nasopharyngeal carcinoma (NPC) treatment.
• DDP sensitivity and side effects are significant challenges in NPC therapy.
• Cancer-associated fibroblasts (CAFs) role in DDP resistance is not fully understood.

Purpose of the Study:

• To investigate how CAFs modulate DDP sensitivity in NPC via ferroptosis.
• To elucidate the molecular mechanisms underlying CAF-mediated regulation of DDP-induced ferroptosis.

Main Methods:

• In vitro studies using NPC cell lines and CAFs.
• In vivo xenograft models in mice.
• Analysis of ferroptosis induction, FGF5 secretion, FGFR2 binding, and Keap1/Nrf2/HO-1 signaling pathway activation.

Main Results:

• DDP induced ferroptosis in NPC cells and inhibited tumor growth in vivo.
• CAFs secreted FGF5, which inhibited DDP-induced ferroptosis in NPC cells.
• FGF5 from CAFs bound to FGFR2 in NPC cells, activating the Keap1/Nrf2/HO-1 pathway.
• FGFR2 overexpression and CAFs protected NPC cells from DDP-induced ferroptosis via the FGF5/FGFR2 axis.

Conclusions:

• CAFs decrease DDP sensitivity in NPC by inhibiting ferroptosis through the FGF5/FGFR2/Nrf2 signaling pathway.
• Targeting the FGF5/FGFR2 axis presents a potential therapeutic strategy to enhance DDP sensitivity and reduce side effects in NPC treatment.