Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization.
- 1State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
- 2State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. [email protected].
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.
Related
- PATZ1 remodels the nucleosome landscape to promote chromatin accessibility in injured neurons
- Cellular, chromatin-accessibility, and spatial contextualization of bulk transcriptional patterns linked to positive peritoneal cytology in endometrial cancer
- Genetic integration reveals causal effects of chromatin accessibility on nucleosome positioning across diverse muscle cells
- Protocol for profiling chromatin accessibility in human small-cell lung cancer FFPE-derived samples using Omni-ATAC-seq
- SMCHD1 loss rewires MYOD1 enhancer nexuses and chromatin accessibility landscapes in muscle cells
BibTeX
@article{jin2026endothelial,
title = {{Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization.}},
author = {Bei Jin and Shenglan Liu and Hongke Huang and Luo Yang and Dong Wei and Wei Dai and Jingfeng Zhou and Yun Wang and Ping Zhang and Qianyun Ye and Jingxuan Pan},
journal = {Signal transduction and targeted therapy},
year = {2026},
month = oct,
doi = {10.1038/s41392-026-02876-1},
url = {https://europepmc.org/article/MED/42894010},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Endothelial exosomes remodel chromatin accessibility and superenhancer in cancer cells to promote liver metastatic colonization.
AU - Bei Jin
AU - Shenglan Liu
AU - Hongke Huang
AU - Luo Yang
AU - Dong Wei
AU - Wei Dai
AU - Jingfeng Zhou
AU - Yun Wang
AU - Ping Zhang
AU - Qianyun Ye
AU - Jingxuan Pan
PY - 2026
DA - 2026/10/19
JO - Signal transduction and targeted therapy
DO - 10.1038/s41392-026-02876-1
UR - https://europepmc.org/article/MED/42894010
AB - 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.
SN - 2095-9907
SN - 2059-3635
ER -