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KAIST Identifies New Therapeutic Target by Revealing How Cancer ‘Hijacks’ the 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, 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.
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.
2026.07.01 View 1355 -
KAIST team links early life epigenetic memory to adult brain inflammation
<(From left) Professor Won-Suk Chung, Ph.D. Ph.D candidate Hyeonji Park Dr. Seongwan Park, Professor Inkyung Jung>
Why do some people remain healthy through childhood yet become more vulnerable to brain disorders such as dementia later in life? A KAIST (President Kwang Hyung Lee) -led team has uncovered a key part of the answer: a developmental ‘switch’ in astrocytes—the brain’s most abundant support cells that shapes how strongly the brain’s immune system reacts in adulthood. The study identifies a gene, NR3C1 (encoding the glucocorticoid receptor), as a master regulator of this switch and shows how early-life epigenetic ‘memory’ can predispose the adult brain to excessive inflammation.
The work was carried out by a joint team led by Professor Inkyung Jung (Department of Biological Sciences, KAIST) and Associate Director Won-Suk Chung (Center for Vascular Research, Institute for Basic Science; Professor, KAIST Biological Sciences). Using mouse models, the researchers mapped gene-regulatory programs across multiple stages of astrocyte development and found that NR3C1 acts during a brief early-postnatal window to enforce long-term immune restraint.
<The schematic illustrates how the NR3C1 gene (glucocorticoid receptor) suppresses the immune response of astrocytes. In normal (control) astrocytes, NR3C1 binds to specific regulatory regions of DNA (nGRE) to inhibit the expression of immune-related genes, thereby maintaining brain homeostasis even under immune stimulation. In contrast, in NR3C1-deficient astrocytes (KO), this suppression is lost, leading to excessive activation of inflammation-related genes such as Gfap, Il6st, Stat2, and Cxcl10. As a result, in an autoimmune encephalomyelitis (EAE) model, pronounced neuroinflammation and clinical symptoms (paralysis and severe debilitation) are observed>
To build this map, the team combined state-of-the-art 3D epigenome profiling with RNA sequencing and chromatin accessibility analyses, capturing how DNA folds and which regulatory elements contact target genes. They identified 55 stage-specific transcription factors that guide astrocyte maturation; among them, NR3C1 emerged as the critical ‘switch’ in early life. Notably, deleting NR3C1 in astrocytes did not disrupt normal development. However, when the adult mice were challenged with an autoimmune model of multiple sclerosis, animals lacking astrocytic NR3C1 mounted exaggerated inflammatory responses and developed more severe disease.
Mechanistically, the study shows that early loss of NR3C1 epigenetically primes immune genes - keeping their regulatory elements open and ready - so that later in life these genes respond too strongly to inflammatory cues. In effect, NR3C1 serves as an early ‘brake’ that prevents over-activation of astrocyte immune programs in adulthood.
“This is the first demonstration that astrocyte immune functions are governed by epigenetic memory,” said Professor Won-Suk Chung. “Our findings offer new clues to the origins of degenerative brain disorders, including Alzheimer’s disease.”
“We reveal a temporal regulatory window in astrocyte development that can set the stage for disease vulnerability in adulthood,” added Professor Inkyung Jung. “Understanding the 3D genome logic behind these programs could open paths to therapies for immune-related brain disorders such as multiple sclerosis.”
<The figure shows the three-dimensional genome structure of astrocytes at specific gene loci, illustrating how NR3C1 regulates their expression. In normal cells, NR3C1 binds to DNA and maintains the chromatin in a closed state, thereby preventing unnecessary activation between distal regulatory elements (enhancers) and gene promoters. In contrast, when NR3C1 is absent, the chromatin becomes open, creating a state in which enhancers and genes can be more easily activated. As a result, genes such as Mxi1 are overexpressed, triggering inflammatory responses. This clearly demonstrates that NR3C1 plays an essential role in maintaining immune homeostasis by stabilizing three-dimensional gene regulatory mechanisms.>
The results of this study were published online on September 22 in the international journal Nature Communications (IF 15.7), with Dr. Seongwan Park and PhD student Hyeonji Park of KAIST’s Department of Biological Sciences as co-first authors.
※ Paper title: “NR3C1-mediated epigenetic regulation suppresses astrocytic immune responses in mice,” DOI: https://www.nature.com/articles/s41467-025-64088-5
In addition, on September 17, the journal published a commentary article introducing this research: https://www.nature.com/articles/s41467-025-64102-w
This research was supported by the Suh Kyungbae Science Foundation, the Ministry of Health and Welfare, the Ministry of Science and ICT, and IBS.
Glossary - Epigenetic priming: preparing genes for rapid future activation by altering chromatin without changing DNA sequence
2025.09.25 View 5373