---
title: "Endothelial exosomes reshape chromatin and superenhancers to promote liver metastasis"
id: "pubmed-42894010"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42894010"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42894010/"
doi: "10.1038/s41392-026-02876-1"
published_at: "2026-10-19T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Endothelial exosomes reshape chromatin and superenhancers to promote liver metastasis
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42894010
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42894010/)
- **DOI:** [10.1038/s41392-026-02876-1](https://doi.org/10.1038%2Fs41392-026-02876-1)
- **Published At:** 2026-10-19T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- The study tested whether pioneer transcription factors increase chromatin accessibility and remodel **superenhancer** (SE) architecture to drive liver colonization-associated phenotypes in cancer cells. - Investigators used ATAC-seq and ChIP-seq to measure chromatin accessibility and SE remodeling after modulation of the pioneer TF **KLF4**. - Data indicated that **KLF4** increased chromatin accessibility and altered SEs, which coincided with higher transcription of SE-associated genes **MCL1** and **RASGRP3**. - Upregulation of **MCL1** and **RASGRP3** was linked by the authors to enhanced proliferation, motility, and metastatic potential in experimental models. - The study reported that endothelial-cell–derived exosomes containing **RN7SL2** promoted **KLF4** expression in uveal melanoma (UM) cells, connecting the endothelial niche to tumor chromatin remodeling. - Clinical dataset analyses showed that overexpression of **RIG-I**, **STAT1**, **KLF4**, and **RASGRP3** individually correlated with shorter metastasis-free survival or overall survival in patients with UM and PDAC, according to the authors. - The authors proposed an exoRN7SL2–**STAT1**–**KLF4**–SEs–**RASGRP3** signaling axis as a model for liver colonization promoted by tumor–endothelium interactions. - The report did not provide clinical dosing, therapeutic interventions, or prospective clinical-trial data; mechanistic and translational validation beyond the described experimental systems was not reported in the abstract.
## Clinical Analysis & Structured Key Points
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Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization [Bei Jin](https://pubmed.ncbi.nlm.nih.gov/?term=Jin+B&cauthor_id=42894010)[#](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Shenglan Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+S&cauthor_id=42894010)[#](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Hongke Huang](https://pubmed.ncbi.nlm.nih.gov/?term=Huang+H&cauthor_id=42894010)[#](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Luo Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+L&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Dong Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+D&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Wei Dai](https://pubmed.ncbi.nlm.nih.gov/?term=Dai+W&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Jingfeng Zhou](https://pubmed.ncbi.nlm.nih.gov/?term=Zhou+J&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Yun Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Y&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Ping Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+P&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Qianyun Ye](https://pubmed.ncbi.nlm.nih.gov/?term=Ye+Q&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Jingxuan Pan](https://pubmed.ncbi.nlm.nih.gov/?term=Pan+J&cauthor_id=42894010)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#full-view-affiliation-2 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. panjx2@mail.sysu.edu.cn.") Affiliations Expand ### Affiliations * 1 State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. * 2 State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. panjx2@mail.sysu.edu.cn. # Contributed equally. * PMID: **42894010** * DOI: [ 10.1038/s41392-026-02876-1 ](https://doi.org/10.1038/s41392-026-02876-1) Item in Clipboard # Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization Bei Jin et al. Signal Transduct Target Ther. 2026. Show details Display options Display options Format Abstract PubMed PMID Signal Transduct Target Ther Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Signal+Transduct+Target+Ther%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Signal+Transduct+Target+Ther%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42894010/) . 2026 Oct 19;11(1):453. doi: 10.1038/s41392-026-02876-1. ### Authors [Bei Jin](https://pubmed.ncbi.nlm.nih.gov/?term=Jin+B&cauthor_id=42894010)[#](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Shenglan Liu](https://pubmed.ncbi.nlm.nih.gov/?term=Liu+S&cauthor_id=42894010)[#](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Hongke Huang](https://pubmed.ncbi.nlm.nih.gov/?term=Huang+H&cauthor_id=42894010)[#](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-equal-contrib-explanation "Contributed equally")[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Luo Yang](https://pubmed.ncbi.nlm.nih.gov/?term=Yang+L&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Dong Wei](https://pubmed.ncbi.nlm.nih.gov/?term=Wei+D&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Wei Dai](https://pubmed.ncbi.nlm.nih.gov/?term=Dai+W&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Jingfeng Zhou](https://pubmed.ncbi.nlm.nih.gov/?term=Zhou+J&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Yun Wang](https://pubmed.ncbi.nlm.nih.gov/?term=Wang+Y&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Ping Zhang](https://pubmed.ncbi.nlm.nih.gov/?term=Zhang+P&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Qianyun Ye](https://pubmed.ncbi.nlm.nih.gov/?term=Ye+Q&cauthor_id=42894010)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-1 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China."), [Jingxuan Pan](https://pubmed.ncbi.nlm.nih.gov/?term=Pan+J&cauthor_id=42894010)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42894010/#short-view-affiliation-2 "State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. panjx2@mail.sysu.edu.cn.") ### Affiliations * 1 State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. * 2 State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. panjx2@mail.sysu.edu.cn. # Contributed equally. * PMID: **42894010** * DOI: [ 10.1038/s41392-026-02876-1 ](https://doi.org/10.1038/s41392-026-02876-1) Item in Clipboard Cite Display options Display options Format Abstract PubMed PMID Linked Discoveries ## Abstract Liver-organotropic metastasis occurs in cancers such as uveal melanoma (UM) and pancreatic ductal adenocarcinoma (PDAC) and is a leading cause of mortality at the terminal stage. Colonization is a rate-limiting and converging step in the metastatic cascade. The drivers underlying liver colonization have largely remained elusive. In this report, we hypothesized that pioneer transcription factors (TFs) increase chromatin accessibility and superenhancer (SE) remodeling, which subsequently promote colonization-associated cellular features [e.g., proliferation, survival, cancer stem cells (CSCs), motility] by driving the transcription of the respective SE-associated genes. We tested this hypothesis and discovered that the pioneer TF KLF4 promoted chromatin accessibility and SE remodeling by ATAC-seq and ChIP-seq. Chromatin accessibility and SE remodeling significantly increased the transcription of the SE-associated genes MCL1 and RASGRP3, which consequently promoted proliferation, motility, and metastasis. Furthermore, the upregulation of KLF4 expression in UM cells was promoted by RN7SL2-containing exosomes from surrounding endothelial cells. Analysis of clinical datasets revealed that the overexpression of RIG-I, STAT1, KLF4, and RASGRP3 was individually correlated with shorter metastasis-free survival or overall survival in patients with UM and PDAC. In conclusion, the identification of the exoRN7SL2-STAT1-KLF4-SEs-RASGRP3 signaling axis may help elucidate metastatic colonization through interactions between tumor cells and the endothelial niche and may yield novel and viable therapeutic targets. © 2026. The Author(s). [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Competing interests: The authors declare no competing interests. ## References 1. 1. Ganesh, K. & Massague, J. Targeting metastatic cancer. Nat Med. 27, 34–44 (2021). - [DOI](https://doi.org/10.1038/s41591-020-01195-4) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/33442008/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/7895475/) 2. 1. Chen, L. & Huang, M. Oncometabolites in cancer: from cancer cells to the tumor microenvironment. Holist Integr Oncol. 3, 16 (2024). 3. 1. Obenauf, A. C. & Massague, J. Surviving at a distance: organ-specific metastasis. Trends Cancer. 1, 76–91 (2015). - [PubMed](https://pubmed.ncbi.nlm.nih.gov/28741564/) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/4673677/) - [DOI](https://doi.org/10.1016/j.trecan.2015.07.009) 4. 1. Shields, C. L. et al. Metastasis of uveal melanoma millimeter-by-millimeter in 8033 consecutive eyes. Arch Ophthalmol. 127, 989–998 (2009). - [PubMed](https://pubmed.ncbi.nlm.nih.gov/19667335/) - [DOI](https://doi.org/10.1001/archophthalmol.2009.208) 5. 1. Siegel, R. L., Miller, K. D., Wagle, N. S. & Jemal, A. Cancer statistics, 2023. CA Cancer J Clin. 73, 17–48 (2023). - [PubMed](https://pubmed.ncbi.nlm.nih.gov/36633525/) Show all 67 references ## MeSH terms * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42894010/) * Carcinoma, Pancreatic Ductal* / genetics Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Carcinoma%2C+Pancreatic+Ductal%2Fgenetics%22%5BMAJR%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Carcinoma%2C+Pancreatic+Ductal) * [ Add to Search ](https://p
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