Hippo Pathway Drives Durable Non-Cell-Autonomous Ferroptosis Resistance in Lung Cancer.

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) promote lung cancer but increase ferroptosis sensitivity.
• The mechanism of ferroptosis evasion in YAP/TAZ-high lung cancer cells is not fully understood.

Purpose of the Study:

• To investigate how YAP/TAZ-high lung cancer cells evade ferroptosis.
• To elucidate the non-cell-autonomous mechanisms of ferroptosis resistance in lung cancer.

Main Methods:

• Coculture of murine lung carcinoma cells with varying YAP/TAZ levels.
• Analysis of ferroptosis resistance, gene expression (Gch1), metabolite synthesis (BH4), and metastatic seeding in vivo.
• Use of conditioned medium and genetic deletion of Gch1 to confirm mechanism.

Main Results:

• YAP/TAZ-low cells induce stable, contact-independent ferroptosis resistance in neighboring YAP/TAZ-high cells.
• This resistance is mediated by GTP cyclohydrolase 1 (GCH1) upregulation, leading to increased antioxidant tetrahydrobiopterin (BH4) synthesis.
• GCH1 is essential for this intercellular ferroptosis resistance program and enhances metastatic potential.

Conclusions:

• A novel Hippo pathway-linked mechanism confers ferroptosis resistance in lung cancer.
• Intra-tumoral heterogeneity in YAP/TAZ activity promotes metastasis through intercellular antioxidant signaling.