Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.

IF 23.3 1区医学 Q1 CELL & TISSUE ENGINEERING

Cell stem cell Pub Date : 2026-06-22 DOI:10.1016/j.stem.2026.05.013

Saori Goto,Vikram Deshpande,Ömer H Yilmaz,Norihiro Goto

{"title":"Lineage plasticity driven by GATA6 loss fuels colorectal cancer metastasis.","authors":"Saori Goto,Vikram Deshpande,Ömer H Yilmaz,Norihiro Goto","doi":"10.1016/j.stem.2026.05.013","DOIUrl":null,"url":null,"abstract":"Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the genetic and epigenetic drivers underlying this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis-derived organoids. Integrative RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs. Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5- cell generation. This reprogramming is mediated by the direct repression of HNF4A and increased H3K27ac and occurs independently of SOX17. Together, these findings identify GATA6 loss as a central regulator of multilineage plasticity that drives liver metastasis in CRC.","PeriodicalId":9665,"journal":{"name":"Cell stem cell","volume":"29 1","pages":""},"PeriodicalIF":23.3000,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell stem cell","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.stem.2026.05.013","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL & TISSUE ENGINEERING","Score":null,"Total":0}

引用次数: 0

Abstract

Colorectal cancer (CRC) liver metastases are the leading cause of CRC-related mortality, yet the genetic and epigenetic drivers underlying this process remain poorly understood. Here, we established a pro-metastatic CRC organoid library through serial orthotopic transplantation of liver metastasis-derived organoids. Integrative RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) analyses identified a pro-metastatic signature characterized by multilineage plasticity, including fetal-like and basal-like/squamous transcriptional programs. Motif and transcription factor activity analyses identified GATA6 as a key regulator of these epigenetic alterations. GATA6 expression is downregulated in liver metastases, and its genetic ablation enhances liver metastasis with minimal effects on primary tumor growth. Mechanistically, GATA6 loss triggers pro-metastatic transcriptional programs, including fetal-like and basal-like/squamous states, accompanied by LGR5- cell generation. This reprogramming is mediated by the direct repression of HNF4A and increased H3K27ac and occurs independently of SOX17. Together, these findings identify GATA6 loss as a central regulator of multilineage plasticity that drives liver metastasis in CRC.

查看原文本刊更多论文

由GATA6缺失驱动的谱系可塑性促进结直肠癌转移。

结直肠癌（CRC）肝转移是CRC相关死亡的主要原因，然而这一过程背后的遗传和表观遗传驱动因素仍然知之甚少。在这里，我们通过肝转移源类器官的连续原位移植建立了一个促转移性CRC类器官库。综合RNA测序（RNA-seq）和转座酶可及染色质测序（ATAC-seq）分析发现了一个以多谱系可塑性为特征的促转移特征，包括胎儿样和基底样/鳞状转录程序。基序和转录因子活性分析表明GATA6是这些表观遗传改变的关键调节因子。GATA6在肝转移中表达下调，其基因消融促进肝转移，对原发肿瘤生长影响最小。从机制上讲，GATA6的缺失触发了促转移性转录程序，包括胎儿样和基底样/鳞状状态，伴随着LGR5细胞的产生。这种重编程是通过直接抑制HNF4A和增加H3K27ac介导的，并且独立于SOX17发生。总之，这些发现确定了GATA6缺失是多谱系可塑性的中心调节因子，驱动结直肠癌的肝转移。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Cell stem cell 生物-细胞生物学

CiteScore

37.10

自引率

2.50%

发文量

151

审稿时长

42 days

期刊介绍： Cell Stem Cell is a comprehensive journal covering the entire spectrum of stem cell biology. It encompasses various topics, including embryonic stem cells, pluripotency, germline stem cells, tissue-specific stem cells, differentiation, epigenetics, genomics, cancer stem cells, stem cell niches, disease models, nuclear transfer technology, bioengineering, drug discovery, in vivo imaging, therapeutic applications, regenerative medicine, clinical insights, research policies, ethical considerations, and technical innovations. The journal welcomes studies from any model system providing insights into stem cell biology, with a focus on human stem cells. It publishes research reports of significant importance, along with review and analysis articles covering diverse aspects of stem cell research.