TGF-β signaling redirects Sox11 gene regulatory activity to promote partial EMT and collective invasion of oncogenically transformed intestinal organoids.

IF 5.9 2区 医学 Q1 ONCOLOGY
Yu-Hsiang Teng, Bismark Appiah, Geoffroy Andrieux, Monika Schrempp, Katja Rose, Angelika Susanna Hofmann, Manching Ku, Sven Beyes, Melanie Boerries, Andreas Hecht
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引用次数: 0

Abstract

Cancer cells infiltrating surrounding tissue frequently undergo partial epithelial-mesenchymal transitions (pEMT) and employ a collective mode of invasion. How these phenotypic traits are regulated and interconnected remains underexplored. Here, we used intestinal organoids with colorectal cancer (CRC) driver mutations as model system to investigate the mechanistic basis of TGF-β1-induced pEMT and collective invasion. By scRNA-seq we identified multiple cell subpopulations representing a broad pEMT spectrum, where the most advanced pEMT state correlated with the transcriptional profiles of leader cells in collective invasion and a poor prognosis mesenchymal subtype of human CRC. Bioinformatic analyses pinpointed Sox11 as a transcription factor gene whose expression peaked in the potential leader/pEMThigh cells. Immunofluorescence staining confirmed Sox11 expression in cells at the invasive front of TGF-β1-treated organoids. Loss-of-function and overexpression experiments showed that Sox11 is necessary, albeit not sufficient, for TGF-β1-induced pEMT and collective invasion. In human CRC samples, elevated SOX11 expression was associated with advanced tumor stages and worse prognosis. Unexpectedly, aside from orchestrating the organoid response to TGF-β1, Sox11 controlled expression of genes related to normal gut function and tumor suppression. Apparently, Sox11 is embedded in several distinct gene regulatory circuits, contributing to intestinal tissue homeostasis, tumor suppression, and TGF-β-mediated cancer cell invasion.

TGF-β信号重定向Sox11基因调控活性,促进部分EMT和肿瘤转化的肠道类器官的集体侵袭。
浸润周围组织的癌细胞经常经历部分上皮-间质转化(ppt),并采用集体侵袭模式。这些表型特征是如何被调节和相互联系的仍未得到充分研究。本研究以结肠直肠癌(CRC)驱动突变的肠道类器官为模型系统,探讨TGF-β1诱导ppt和集体侵袭的机制基础。通过scRNA-seq,我们鉴定了多个细胞亚群,代表了广泛的pEMT谱,其中最先进的pEMT状态与集体侵袭中领导细胞的转录谱和预后不良的人CRC间充质亚型相关。生物信息学分析确定Sox11是一个转录因子基因,其表达在潜在的领导者/pEMThigh细胞中达到峰值。免疫荧光染色证实了TGF-β1处理的类器官侵袭前细胞中Sox11的表达。功能缺失和过表达实验表明,Sox11对于TGF-β1诱导的pEMT和集体侵袭是必要的,尽管不是充分的。在人类结直肠癌样本中,SOX11表达升高与肿瘤分期晚期和预后较差相关。出乎意料的是,除了协调对TGF-β1的类器官反应外,Sox11还控制着正常肠道功能和肿瘤抑制相关基因的表达。显然,Sox11嵌入在几个不同的基因调控回路中,参与肠组织稳态、肿瘤抑制和TGF-β介导的癌细胞侵袭。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Oncogenesis
Oncogenesis ONCOLOGY-
CiteScore
11.90
自引率
0.00%
发文量
70
审稿时长
26 weeks
期刊介绍: Oncogenesis is a peer-reviewed open access online journal that publishes full-length papers, reviews, and short communications exploring the molecular basis of cancer and related phenomena. It seeks to promote diverse and integrated areas of molecular biology, cell biology, oncology, and genetics.
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