FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Phosphoinositide 3-kinase (PI3K)-AKT signaling is integral to cancer development.
• Mammalian Forkhead box O (FoxO) transcription factors (FoxO1, FoxO3, FoxO4) are downstream effectors of PI3K-AKT signaling.
• The role of FoxOs in PI3K-AKT-driven neoplastic phenotypes requires investigation.

Purpose of the Study:

• To genetically analyze the function of mammalian FoxO transcription factors in cancer development.
• To determine if FoxOs act as tumor suppressors in the context of PI3K-AKT pathway activation.
• To identify FoxO-regulated genes and pathways involved in endothelial cell function and vascular homeostasis.

Main Methods:

• Genetic deletion of FoxO alleles in mice (germline and somatic).
• Transcriptome and promoter analyses of affected endothelial cells.
• Functional studies on identified FoxO targets, including Sprouty2 and PBX1.

Main Results:

• Deletion of up to five FoxO alleles resulted in modest neoplastic phenotypes.
• Broad somatic deletion of all FoxOs led to a progressive cancer-prone state, including thymic lymphomas and hemangiomas.
• FoxO regulation of target genes in vivo is context-specific.
• Sprouty2 and PBX1 were validated as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.

Conclusions:

• Mammalian FoxOs are bona fide tumor suppressors.
• FoxO transcription factors play a critical role in preventing cancer development.
• FoxO-mediated regulation is essential for maintaining vascular homeostasis and endothelial cell function.