Cancer-Associated Fibroblasts are the Main Source of Epithelial-to-Mesenchymal Signaling in the Tumor Microenvironment. Cancer-Associated Fibroblasts are the Main Source of Epithelial-to-Mesenchymal Signaling in the Tumor Microenvironment

Epithelial-to-mesenchymal transition (EMT) is associated with tumor initiation, metastasis, and drug resistance. However, the mechanisms underlying these associations are largely unknown. We studied several tumor types to identify the source of EMT gene expression signals and to illuminate mechanisms of resistance to immuno-oncology treatment. Across tumor types, EMT-related gene expression was strongly associated with expression of stroma-related genes. Based on RNA sequencing of multiple patient-derived xenograft models, EMT-related gene expression was enriched in the stroma versus parenchyma. EMT-related markers were predominantly expressed by cancer-associated fibroblasts (CAFs), cells of mesenchymal origin which produce a variety of matrix proteins and growth factors. Scores derived from a 3-gene CAF transcriptional signature (COL1A1, COL1A2, COL3A1) were sufficient to reproduce association between EMT-related markers and disease prognosis. Our results suggest that CAFs are the primary source of EMT signaling and have potential roles as biomarkers and targets for immuno-oncology therapies. Overall design: Comparative gene expression profiling of patient-derived xenografts for multi-cancer cohort using RNA-seq assay *** Submitter declares that the patients from which these files have been derived have not consented to the raw data public release but processed data is allowed. ***

上皮间质转化（Epithelial-to-mesenchymal transition, EMT）与肿瘤发生、转移及药物耐药性密切相关，但其关联背后的分子机制在很大程度上尚不明确。
本研究针对多种肿瘤类型展开研究，旨在明确EMT基因表达信号的来源，并阐明肿瘤免疫治疗耐药的相关机制。
跨肿瘤类型分析显示，EMT相关基因表达与基质相关基因的表达呈显著相关性。
基于多个患者来源异种移植模型的RNA测序结果，EMT相关基因表达在基质组分中较实质组分更为富集。
EMT相关标志物主要由癌相关成纤维细胞（cancer-associated fibroblasts, CAFs）表达，这类细胞起源于间质，可分泌多种基质蛋白与生长因子。
基于COL1A1、COL1A2、COL3A1这3个基因组成的CAF转录特征计算得到的评分，足以复现EMT相关标志物与疾病预后之间的关联。
本研究结果表明，CAFs是EMT信号的主要来源，有望成为肿瘤免疫治疗的生物标志物与治疗靶点。
研究设计：本研究采用RNA测序技术，对多癌队列的患者来源异种移植模型开展比较基因表达谱分析。
提交者声明：本数据集相关文件的供体患者未同意原始数据公开，但允许发布处理后的数据。