Selective Targeting of Tip Endothelial Cells as a Therapeutic Strategy for Tumor Angiogenesis

Tip endothelial cells (^TipEC), the leading edge of angiogenic sprouts, are essential for pathological neo-vascularization but remain difficult to target due to the lack of specific druggable markers. Here, we identify Doppel as a selective and druggable regulator of endothelial tip cell function. Doppel expression enhances ^TipEC selection, directional migration, and regulates tip-stalk cell dynamics by spatially controlling VEGFR2/Dll4/Src pathway. Genetic ablation of PRND (Doppel) reduces tip cell formation without affecting the stalk cells (^StalkECs) number in tumors, indicating its selective role in ^TipECs. Importantly, depletion of ^TipECs using the first-in-class monoclonal antibodies against a highly conserved WQF-motif of Doppel robustly decreased the growth of tumors by selectively downregulating VEGFR2+ ^TipECs but not ^StalkECs. These findings position Doppel as a tumor ^TipEC-specific, druggable target that may offer a new avenue to enhance and refine anti-angiogenic therapies in cancer treatment.