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journal article·2026-03Open access

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

Byoungmo Kim, Ha Kyeong Lee, Zulfikar Azam, Jeong Uk Choi, Riajul Wahab, Na Kyeong Lee, Yoon Gun Ko, So‐Young Choi, Se‐Ra Lee, Wan Seob Shim, Taeeung Kim, In‐San Kim, Farzana Alam, Sang Yoon Kim, Seong Who Kim, Youngro Byun, Taslim A Al‐Hilal

Advanced Science· Volume 13· Issue 18
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Source abstract

Abstract

ABSTRACT Tip endothelial cells ( Tip EC), 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 Tip EC 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 ( Stalk ECs) number in tumors, indicating its selective role in Tip ECs. Importantly, depletion of Tip ECs 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+ Tip ECs but not Stalk ECs. These findings position Doppel as a tumor Tip EC‐specific, druggable target that may offer a new avenue to enhance and refine anti‐angiogenic therapies in cancer treatment.
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Research context

OpenAlex topics: Angiogenesis and VEGF in Cancer · Cell Adhesion Molecules Research · Hippo pathway signaling and YAP/TAZ

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

College of Pharmacy and Research Institute of Pharmaceutical Sciences Seoul National University Seoul Republic of Korea

Department of Molecular Pharmaceutics and Biomedical Engineering University of Utah Salt Lake City Utah USA

College of Pharmacy Kyung Hee University Seoul Republic of Korea

College of Pharmacy and Research Institute for Drug Development Pusan National University Busan Republic of Korea

Pharosgen Co. Ltd Seoul Republic of Korea

New Drug Development Center Osong Medical Innovation Foundation 123 Osongsaengmyeong‐ro Heungdeok‐gu Cheongju Chungbuk Republic of Korea

KU‐KIST Graduate School of Converging Science and Technology Korea University Seoul Republic of Korea

Department of Pharmacology and Toxicology University of Utah Salt Lake City Utah USA

Asan Medical Center University of Ulsan College of Medicine Seoul South Korea

Funding

Lizanell and Colbert Coldwell Foundation · DOD Peer Reviewed Cancer Research Program · Small Business Technology Transfer · National Institute of General Medical Sciences · National Cancer Institute · Korea Drug Development Fund

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