2. Academic Validation
  3. FOXF1 promotes tumor vessel normalization and prevents lung cancer progression through FZD4

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

  • EMBO Mol Med. 2024 May;16(5):1063-1090. doi: 10.1038/s44321-024-00064-8.
Fenghua Bian # 1,  Chinmayee Goda # 1,  Guolun Wang # 1,  Ying-Wei Lan 1 2,  Zicheng Deng 1 2,  Wen Gao 2,  Anusha Acharya 1,  Abid A Reza 1,  Jose Gomez-Arroyo 1,  Nawal Merjaneh 3,  Xiaomeng Ren 4,  Jermaine Goveia 5,  Peter Carmeliet 5 6,  Vladimir V Kalinichenko 2 7,  Tanya V Kalin 8 9 10 11
Affiliations

Affiliations

  • 1 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
  • 2 Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, 475 N 5th Street, Phoenix, AZ, 85004, USA.
  • 3 Center for Cancer and Blood Disorders, Phoenix Children's Hospital, 1919 E Thomas Rd., Phoenix, AZ, 85016, USA.
  • 4 Division of Asthma Research of Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA.
  • 5 Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, Leuven, 3000, Belgium.
  • 6 Center for Biotechnology, Khalifa University of Science and Technology, Abu Dhabi, UAE.
  • 7 Division of Neonatology, Phoenix Children's Hospital, 1919 E Thomas Rd., Phoenix, AZ, 85016, USA.
  • 8 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA. tatianakalin@arizona.edu.
  • 9 Department of Child Health, Phoenix Children's Research Institute, University of Arizona College of Medicine-Phoenix, 475 N 5th Street, Phoenix, AZ, 85004, USA. tatianakalin@arizona.edu.
  • 10 Center for Cancer and Blood Disorders, Phoenix Children's Hospital, 1919 E Thomas Rd., Phoenix, AZ, 85016, USA. tatianakalin@arizona.edu.
  • 11 Department of Internal Medicine, Division of Pulmonary and Critical Care, University of Arizona College of Medicine-Phoenix, 475 N 5th Street, Phoenix, AZ, 85004, USA. tatianakalin@arizona.edu.
  • # Contributed equally.
PMID: 38589650 DOI: 10.1038/s44321-024-00064-8
Abstract

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.

Keywords

Foxf1; Fzd4; Nanoparticle Delivery System; Tumor-Associated Endothelial Cells; Wnt Signaling.

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