1. Spliceosome-Targeted Therapies Trigger an Antiviral Immune Response in Triple-Negative Breast Cancer
- Author
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Lacey E. Dobrolecki, Siddhartha Tyagi, Jitendra K. Meena, Fabio Stossi, Swarnima Singh, Matthew J. Ellis, Bing Zhang, William Wu, Ik Sun Kim, Tiffany Y.T. Hsu, George Miles, Calla M. Olson, Jeffrey M. Rosen, Srinivas Chamakuri, Kristen L. Karlin, Heyuan Li, Damian W. Young, Nicholas J. Neill, Sarah J. Kurley, Alexander B. Saltzman, Xiang Zhang, Gino M. Canlas, Elizabeth A. Bowling, Hsiang-Ching Chung, Silvia Buonamici, Ido Golding, Michael T. Lewis, Thomas F. Westbrook, Rocio Dominguez-Vidana, Mayra Orellana, Charles Y. Lin, Anna Malovannaya, Fade Gong, Lihua Yu, Lukas M. Simon, Jarey H. Wang, and Julien Dubrulle
- Subjects
0303 health sciences ,Spliceosome ,Innate immune system ,RNA ,Cancer ,Biology ,Adaptive Immunity ,medicine.disease ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,RNA silencing ,0302 clinical medicine ,Immune system ,RNA splicing ,Cancer research ,medicine ,Spliceosomes ,030217 neurology & neurosurgery ,Triple-negative breast cancer ,030304 developmental biology ,RNA, Double-Stranded ,Signal Transduction - Abstract
Summary 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.
- Published
- 2021