FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4.
Fenghua BianChinmayee GodaGuolun WangYing-Wei LanZicheng DengWen GaoAnusha AcharyaAbid A RezaJose Gomez-ArroyoNawal MerjanehXiaomeng RenJermaine GoveiaPeter CarmelietVladimir V KalinichenkoTanya V KalinPublished in: EMBO molecular medicine (2024)
Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis. Transcriptional regulators that control the reprogramming of EC into TEC are poorly understood. We identified Forkhead box F1 (FOXF1) as a critical regulator of EC-to-TEC transition. FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific overexpression of FOXF1 normalized tumor vessels and inhibited the progression of lung cancer. FOXF1 deficiency decreased Wnt/β-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/β-catenin signaling in TECs, normalized tumor vessels and inhibited the progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/β-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC.
Keyphrases
- oxidative stress
- endothelial cells
- transcription factor
- small cell lung cancer
- cell proliferation
- gene expression
- high glucose
- poor prognosis
- type diabetes
- healthcare
- newly diagnosed
- machine learning
- blood brain barrier
- end stage renal disease
- binding protein
- prognostic factors
- young adults
- artificial intelligence
- big data
- patient reported outcomes
- heat stress
- quality improvement
- high fat diet induced
- epidermal growth factor receptor
- current status
- smoking cessation