Abstract C14: Foxf1 transcription factor reprograms pulmonary endothelial cells to promote metastasis

The ability to form a metastatic niche is a unique feature of tumor cells. The niche provides signals for tumor cells extravasation, survival, dormancy or proliferation, ultimately leading to the formation of metastasis. Endothelial cells of metastatic niche become activated and play a key role in tumor cells extravasation and establishing inflammatory microenvironment that supports metastatic outgrowth. Although multiple signaling pathways have been implicated in formation of metastatic niche, the transcriptional network which controls reprogramming of normal endothelial cells (EC) into activated endothelial cells of the metastatic niche (aEC) are poorly understood. Screening for multiple regulators of the endothelial reprogramming, we identified Forkhead Box F1 (Foxf1) transcription factor, which is highly expressed in normal pulmonary ECs and is down-regulated in aECs within mouse and human lung metastases. Tamoxifen-regulated inactivation of both Foxf1 alleles in EC of adult Pdgfb-CreER/Foxf1fl/fl mice caused lung inflammation and edema, leading to respiratory insufficiency and uniform mortality. Deletion of a single Foxf1 allele from mouse ECs was sufficient to increase the number and size of pulmonary metastases in the spontaneous orthotopic mouse model of breast cancer. Increased lung metastasis in Foxf1-deficient mice was associated with increased recruitment of macrophages to the metastatic niche. The genomic signature of Foxf1 deletion from purified lung ECs indicated increased expression of cell adhesion molecules and pro-inflammatory chemokines, as well as reduced expression of genes critical for maintenance of adherence junctions in ECs. Foxf1 knockdown in vitro and in vivo disrupted adherence junctions, increased endothelial permeability and decreased mRNA and protein levels of VE-cadherin, a key regulator of endothelial barrier function. Foxf1 directly bound to and induced transcriptional activity of the VE-cadherin (Cdh5) promoter through -788/-775 bp Cdh5 promoter region. Altogether, Foxf1 transcription factor controls reprogramming of normal pulmonary ECs into aECs of the metastatic niche by regulating expression of endothelial genes critical for recruitment of macrophages and extravasation of tumor cells through endothelial barrier. Citation Format: Yuqi Cai, Tien Le, David Malewski, Craig Bolte, Chinmayee Goda, Tanya V. Kalin. Foxf1 transcription factor reprograms pulmonary endothelial cells to promote metastasis. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C14.