FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4

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/beta-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/beta-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/beta-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC. Angiogenesis supports tumor growth. Current antiangiogenic therapies have not significantly improved survival; there is a critical need for new approaches. Mechanisms that regulate transition from normal to tumor-associated endothelial cells and drive pathological angiogenesis are poorly understood.FOXF1 is decreased in tumor-associated endothelial cells of NSCLC patients and mouse model of lung cancer. Genetic deletion of FOXF1 gene from endothelial cells increases lung tumor growth and metastasis, whereas transgenic over-expression of FOXF1 decreases lung tumor growth and metastasis. FOXF1-deficient tumor-associated vasculature is structurally and functionally abnormal. Loss of FOXF1 decreases Wnt/beta-catenin signaling in endothelial cells through direct transcriptional activation of Fzd4. Endothelial-specific nanoparticle delivery of FZD4 cDNA normalizes tumor vessels and inhibits lung cancer progression. Angiogenesis supports tumor growth. Current antiangiogenic therapies have not significantly improved survival; there is a critical need for new approaches. Mechanisms that regulate transition from normal to tumor-associated endothelial cells and drive pathological angiogenesis are poorly understood.