FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy

• Published in: Cell reports (Cambridge) 2023-08, Vol.42 (8), p.112791-112791, Article 112791
• Main Authors: Cannell, Ian G., Sawicka, Kirsty, Pearsall, Isabella, Wild, Sophia A., Deighton, Lauren, Pearsall, Sarah M., Lerda, Giulia, Joud, Fadwa, Khan, Showkhin, Bruna, Alejandra, Simpson, Kathryn L., Mulvey, Claire M., Nugent, Fiona, Qosaj, Fatime, Bressan, Dario, Dive, Caroline, Caldas, Carlos, Hannon, Gregory J.
• Format: Article
• Language: English
• Subjects: anti-angiogenic therapy; Cell Line, Tumor; CP: Cancer; epithelial-to-endothelial transistion; Humans; Immunotherapy; Neovascularization, Pathologic - metabolism; transcriptional reprogramming; transdifferentiation; tumor vasculature
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112791

Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood vessels, and their presence is generally associated with poor patient prognosis. Here we show that the transcription factor, Foxc2, promotes VM in diverse solid tumor types by driving ectopic expression of endothelial genes in tumor cells, a process that is stimulated by hypoxia. VM-proficient tumors are resistant to anti-angiogenic therapy, and suppression of Foxc2 augments response. This work establishes co-option of an embryonic endothelial transcription factor by tumor cells as a key mechanism driving VM proclivity and motivates the search for VM-inhibitory agents that could form the basis of combination therapies with anti-angiogenics. [Display omitted] •FOXC2 is upregulated in vasculogenic mimicry (VM)-proficient tumor cells•FOXC2 regulates endothelial genes in tumor cells•Severe hypoxia promotes quasi-endothelial differentiation of tumor cells•FOXC2-driven VM promotes resistance to anti-angiogenic therapy Cannell et al. identify the transcription factor FOXC2 as a driver of vasculogenic mimicry (VM). VM describes the formation of pseudo blood vessels lined by tumor cells that have acquired endothelial-like properties. FOXC2 promotes ectopic expression of endothelial genes in tumor cells and promotes resistance to anti-angiogenic therapies.