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Bioact. Mater., Vol. 67. 2027 | https://doi.org/10.1016/j.bioactmat.2026.08.031 Tissue-derived extracellular matrix hydrogels instruct epigenetic adaptation in metastatic colonization

Heejeong Yoon^{a 1}, Dayoung Kim ^{a 1}, Hye-Jin Jeong ^b, Hohyeon Han ^c, Seon-Jin Kim ^c, Jinah Jang^{c d e}, Deok-Beom Jung ^f, Seung-Jae Myung ^{f g}, Chang Sik Yu ^h, In Ho Song ⁱ, Ju Hae Choi ^a, M. Ryan Corces ^{j k l}, Taejoon Kwon ^{a m n}, Kyungjae Myung ^{a m}, Jinmyoung Joo ^{a m n}, Joo H. Kang ^a, Tae-Eun Park ^a*, Seung Woo Cho ^{a m n*}

^aDepartment of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea
^bCenter for Genome Engineering, Institute for Basic Science, Daejeon, 34126, Republic of Korea
^cDivision of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, 37673, Republic of Korea
^dDepartment of Mechanical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
^eDepartment of Convergence IT Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
^fDigestive Diseases Research Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
^gDepartment of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
^hDivision of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
ⁱDivision of Colorectal Surgery, Department of Surgery, Dongnam Institute of Radiological and Medical Sciences, Busan, 46033, Republic of Korea
^jGladstone Institute of Neurological Disease, San Francisco, CA, 94158, USA
^kGladstone Institute of Data Science and Biotechnology, San Francisco, CA, 94158, USA
^lDepartment of Neurology, University of California San Francisco, San Francisco, CA, 94158, USA
^mCenter for Genomic Integrity, Institute for Basic Science, Ulsan, 44919, Republic of Korea
ⁿGraduate School of Health Science and Technology, Ulsan National Institute of Science and Technology, Ulsan, 44919, Republic of Korea

^*Corresponding Authors: Tae-Eun Park, Seung Woo Cho
¹These authors contributed equally

Abstract

The extracellular matrix (ECM) plays a central role in regulating tumor progression and metastatic colonization by providing biochemical and mechanical signals that shape cancer cell fate. However, most organoid culture systems rely on basement membrane extracts that fail to reproduce the tissue-specific extracellular environments encountered during metastasis. Here, we develop tissue-derived decellularized matrix hydrogels to reconstruct organ-specific microenvironments and investigate epigenetic adaptation to ECM cues during metastatic colonization. Patient-derived colorectal cancer organoids cultured in colon-derived matrices exhibited enhanced maintenance of stem-like phenotypes and colon-specific chromatin accessibility landscapes compared with cultures grown in basement membrane extracts, demonstrating improved physiological relevance for primary tumor modeling. When exposed to matrices derived from secondary organs, the organoids showed distinct growth phenotypes accompanied by rapid, tissue-dependent chromatin accessibility remodeling, indicating that ECM composition alone can reshape regulatory programs governing metastatic adaptation. Notably, liver-derived matrices selectively activated hepatocyte nuclear factor 4 alpha (HNF4A)–associated transcriptional networks and created a context-specific dependence on c-MET signaling for survival. Functional perturbation of HNF4A or c-MET signaling confirmed that both are required for organoid formation specifically within the liver matrix environment. Together, these findings establish tissue-derived matrix hydrogels as instructive bioactive materials that actively regulate cancer cell epigenetic states and reveal microenvironment-specific therapeutic vulnerabilities during early metastatic colonization.

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