生物
剪接体
RNA剪接
免疫系统
癌症研究
RNA沉默
核糖核酸
癌症
选择性拼接
先天免疫系统
三阴性乳腺癌
RNA干扰
乳腺癌
免疫学
信使核糖核酸
遗传学
基因
作者
Elizabeth A. Bowling,Jarey H. Wang,Fade Gong,William Wu,Nicholas J. Neill,Ik Sun Kim,Siddhartha Tyagi,Mayra Orellana,Sarah J. Kurley,Rocío Domínguez-Vidaña,Hsiang-Ching Chung,Tiffany Hsu,Julien Dubrulle,Alexander B. Saltzman,Heyuan Li,Jitendra K. Meena,Gino Martin Canlas,Srinivas Chamakuri,Swarnima Singh,Lukas M. Simon
出处
期刊:Cell
[Cell Press]
日期:2021-01-01
卷期号:184 (2): 384-403.e21
被引量:165
标识
DOI:10.1016/j.cell.2020.12.031
摘要
Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.
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