KAIST

< (From Left) Dr. Andrew J. Lee, Dr. Sunwoo Min, Ph.D. student Su Chan Park, Professor Ji Min Lee, Professor Inkyung Jung >

Anti-angiogenic therapies targeting VEGF have been widely used in cancer treatment, yet their long-term efficacy remains limited. Tumor vascular endothelial cells (TECs) exhibit high adaptive plasticity, enabling them to resist treatment and sustain tumor growth, but the molecular mechanism underlying this plasticity has remained poorly understood.

KAIST, led by President Kwang Hyung Lee, announced that a joint research team led by Professor Inkyung Jung (Department of Biological Sciences), Professor Ji Min Lee (Graduate School of Medical Science and Engineering), and Professor Gou Young Koh (Institute for Basic Science) has now uncovered the answer. By integrating cross-cancer single-cell transcriptomic and epigenomic atlases across eight solid tumor types with multiomic profiles, including 3D chromatin contact maps, of human embryonic stem cell (hESC)-derived vascular endothelial cell differentiation, the team demonstrated that TECs reactivate a gene regulatory program normally confined to the late progenitor stage of vascular development. Much like reusing an old blueprint rather than drawing up a new one, tumors co-opt this pre-existing developmental program to fuel blood vessel growth.

The team’s integrative framework combined single-cell RNA-seq and ATAC-seq across multiple tumor types with H3K27ac ChIP-seq, Hi-C-based 3D chromatin mapping across a dense time series of hESC-to-EC differentiation. This approach resolved the EC-progenitor specific regulatory program that defines the shared pro-angiogenic program between late EC progenitors and TECs.

Within this framework, integrin receptor (ITGAV) emerged as a functional mediator specifically upregulated in both late EC progenitors and TECs. Cell-to-cell interaction analysis identified multiple key ligands from tumor micro enviroment (TME) that reactivate the progenitor-associated gene regulatory program. Pharmacologic inhibition attenuated endothelial migration, invasion, and tube formation in vitro, and significantly reduced tumor vascularization and growth in a colorectal cancer xenograft model in vivo.

< Figure. Research Overview: A New Therapeutic Strategy and Target Validation Based on the Discovery That Tumors Co-opt Gene Regulatory Programs Already Present in Normal Vascular Differentiation to Grow Blood Vessels >

Professor Inkyung Jung noted that this study reframes how we understand tumor angiogenesis: tumors do not invent new mechanisms, but exploit regulatory programs already embedded in normal vascular development. This insight offers a new conceptual basis for why anti-VEGF therapies face limitations, and points toward targeting the underlying regulatory architecture of endothelial plasticity as a complementary anti-angiogenic strategy.

The study was co-first authored by Dr. Andrew J. Lee, Dr. Sunwoo Min, Ph.D. student Su Chan Park; and Dr. Mei-Yu Qiu. Professors Inkyung Jung, Ji Min Lee, and Gou Young Koh served as corresponding authors. The findings were published on June 8 in Cancer Research [IF = 22.3].

※ Paper title: "A Co-opted Developmental Gene Regulatory Program in Endothelial Progenitors Promotes Tumor Angiogenic Phenotypes"
※ DOI: 10.1158/0008-5472.CAN-25-5094
※ Authors: Andrew J. Lee (KAIST, first author), Sunwoo Min (KAIST, co-first), Su Chan Park (KAIST, co-first), Mei-Yu Qiu (IBS, co-first), Gou Young Koh (IBS, co-corresponding), Ji Min Lee (KAIST, co-corresponding), Inkyung Jung (KAIST, corresponding)

This research was supported by the National Research Foundation of Korea and the Institute for Basic Science.