HMN 2026: How New therapeutic target for cancer is identified by revealing how cancer ‘hijacks’ blueprint for blood vessel development

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 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 and 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 the tumor microenvironment (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.

Jung noted that this study reframes how researchers 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. Jung, Lee and Koh served as corresponding authors. The findings were published June 8 in Cancer Research.

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