Disruption of cellular plasticity by repeat RNAs in human pancreatic cancer

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2024-10-08 DOI:10.1016/j.cell.2024.09.024

Eunae You, Patrick Danaher, Chenyue Lu, Siyu Sun, Luli Zou, Ildiko E. Phillips, Alexandra S. Rojas, Natalie I. Ho, Yuhui Song, Michael J. Raabe, Katherine H. Xu, Peter M. Richieri, Hao Li, Natalie Aston, Rebecca L. Porter, Bidish K. Patel, Linda T. Nieman, Nathan Schurman, Briana M. Hudson, Khrystyna North, David T. Ting

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Abstract

Aberrant expression of repeat RNAs in pancreatic ductal adenocarcinoma (PDAC) mimics viral-like responses with implications on tumor cell state and the response of the surrounding microenvironment. To better understand the relationship of repeat RNAs in human PDAC, we performed spatial molecular imaging at single-cell resolution in 46 primary tumors, revealing correlations of high repeat RNA expression with alterations in epithelial state in PDAC cells and myofibroblast phenotype in cancer-associated fibroblasts (CAFs). This loss of cellular identity is observed with dosing of extracellular vesicles (EVs) and individual repeat RNAs of PDAC and CAF cell culture models pointing to cell-cell intercommunication of these viral-like elements. Differences in PDAC and CAF responses are driven by distinct innate immune signaling through interferon regulatory factor 3 (IRF3). The cell-context-specific viral-like responses to repeat RNAs provide a mechanism for modulation of cellular plasticity in diverse cell types in the PDAC microenvironment.

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人胰腺癌中重复 RNA 对细胞可塑性的破坏

胰腺导管腺癌（PDAC）中重复 RNA 的异常表达模拟了病毒样反应，对肿瘤细胞状态和周围微环境的反应产生了影响。为了更好地了解重复 RNA 在人类 PDAC 中的关系，我们对 46 个原发性肿瘤进行了单细胞分辨率的空间分子成像，结果发现重复 RNA 的高表达与 PDAC 细胞上皮状态的改变和癌症相关成纤维细胞（CAFs）的肌成纤维细胞表型有关。通过对 PDAC 和 CAF 细胞培养模型中的细胞外囊泡 (EV) 和单个重复 RNA 进行投药，可以观察到这种细胞特性的丧失，这表明这些病毒样元素在细胞间相互传播。PDAC 和 CAF 反应的差异是由通过干扰素调节因子 3 (IRF3) 发出的不同先天性免疫信号驱动的。细胞对重复 RNA 的特异性病毒样反应为调节 PDAC 微环境中不同细胞类型的细胞可塑性提供了一种机制。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.