A Co-opted Developmental Gene Regulatory Program in Endothelial Progenitors Promotes Tumor Angiogenic Phenotypes.

UNLABELLED: The transition of endothelial cells (EC) to tumor-associated ECs (TEC) is a critical process in tumor progression. The underlying mechanisms driving this angiogenic state could represent potential therapeutic targets. In this study, we revealed that a co-opted gene regulatory program from EC progenitors promotes the angiogenic phenotypes of TECs. Specifically, the TEC-specific gene regulatory program, derived from large-scale single-cell transcriptomic and epigenomic atlases across multiple solid tumors, was projected onto multiomic maps of human embryonic stem cell-derived EC differentiation. TECs reactivated a gene regulatory program governing extracellular matrix remodeling originally confined to the late EC progenitor state. Notably, integrin αv emerged as a mediator associated with endothelial plasticity in the tumor microenvironment (TME). Stimulation of primary ECs with predicted TME ligands reactivated these progenitor-associated regulatory programs, whereas inhibition of integrin αv attenuated this effect, suppressing endothelial migration, invasion, and tumor vascularization in vivo. Collectively, these findings reveal that tumor endothelial plasticity is governed by the co-option of a developmental cis-regulatory program, highlighting a regulatory mechanism underlying TEC adaptation in tumors and providing a rational therapeutic strategy to counteract angiogenic reprogramming.

SIGNIFICANCE: Tumors exploit intrinsic endothelial differentiation programs to drive vascular evolution, providing a conceptual framework for targeting endothelial plasticity as an anti-angiogenic strategy.