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

## TL;DR

This paper identifies Doppel as a key protein in tip endothelial cells that can be targeted to stop tumor blood vessel growth.

## Contribution

The study discovers Doppel as a selective and druggable target for tip endothelial cells in tumor angiogenesis.

## Key findings

- Doppel regulates tip endothelial cell function through the VEGFR2/Dll4/Src pathway.
- Targeting Doppel with monoclonal antibodies reduces tumor growth by selectively affecting tip endothelial cells.
- Genetic ablation of Doppel decreases tip cell formation without impacting stalk cells.

## Abstract

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.

Doppel protein is selectively expressed in tip endothelial cells within the tumor vasculature, where it promotes tip cell motility and stabilizes the tip cell phenotype. Targeting Doppel with monoclonal antibodies disrupts this stabilization, impairs angiogenic sprouting, and reduces tumor angiogenesis, offering a selective and druggable switch for therapeutic vascular targeting.