The formation of new blood vessels is a fundamental aspect of melanoma progression, supplying vital nutrients for tumor growth and enabling tumor cell dissemination. This process is disorganized, resulting in immature and leaky vessels that contribute to the pro-tumorigenic and immunosuppressive tumor microenvironment, further compromising therapy response.
Our research focuses on endovascular progenitors (EVPs), which are mobilized and infiltrate primary melanoma tumors from very early stages to form the new tumor vasculature. They express paracrine factors promoting tumor growth and invasion, as well as SOX9, a key transcription factor distinguishing EVPs from other endothelial populations.
In this study, we investigated how Sox9 deletion in the endothelium affects tumor vascularization, the microenvironment, and metastasis. Sox9 expression was upregulated in tumor endothelial cells of mice harboring melanomas and in human endothelial cells exposed to melanoma conditioned medium. Endothelial-specific conditional knockout of Sox9 (Sox9fl/fl/Cdh5CreERt2/Rosa-YFP) resulted in a significant reduction in tumor growth and metastases. Importantly, despite a significant reduction in the number of CD31+ vessels, there was a significant increase in pericyte coverage, suggesting increased maturity of the remaining vessels. These changes in the endothelium translated into a reduction in hypoxia as demonstrated by decreased GLUT1 and HIF1α expression. RNA sequencing and spatial transcriptomics analysis confirmed the reduced hypoxia and demonstrated a restoration of the immune cell infiltration, validated by immunostaining.
In conclusion, our investigation into Sox9 deletion in the endothelium has revealed promising results, including reduced tumor vascularization, improved vessel maturity, decreased hypoxia, and restored immune cell infiltration, ultimately leading to decreased tumor growth and metastases. Furthermore, this innovative approach, addressing both the structural and functional aspects of blood vessels, holds potential for enhancing immunotherapy outcomes in melanoma and overcoming therapy resistance.