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

Author:

Bian FenghuaORCID,Goda ChinmayeeORCID,Wang Guolun,Lan Ying-Wei,Deng Zicheng,Gao WenORCID,Acharya Anusha,Reza Abid AORCID,Gomez-Arroyo Jose,Merjaneh Nawal,Ren XiaomengORCID,Goveia Jermaine,Carmeliet PeterORCID,Kalinichenko Vladimir V,Kalin Tanya VORCID

Abstract

AbstractCancer 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.

Funder

HHS | NIH | NHLBI | Division of Intramural Research

Publisher

Springer Science and Business Media LLC

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