Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer.

Abstract

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.

• Authors: Elizabeth A Bowling, Jarey H Wang, Fade Gong, William Wu, Nicholas J Neill, Ik Sun Kim, Siddhartha Tyagi, Mayra Orellana, Sarah J Kurley, Rocio Dominguez-Vidaña, Hsiang-Ching Chung, Tiffany Y-T Hsu, Julien Dubrulle, Alexander B Saltzman, Heyuan Li, Jitendra K Meena, Gino M Canlas, Srinivas Chamakuri, Swarnima Singh, Lukas M Simon, Calla M Olson, Lacey E Dobrolecki, Michael T Lewis, Bing Zhang, Ido Golding, Jeffrey M Rosen, Damian W Young, Anna Malovannaya, Fabio Stossi, George Miles, Matthew J Ellis, Lihua Yu, Silvia Buonamici, Charles Y Lin, Kristen L Karlin, Xiang H-F Zhang, Thomas F Westbrook
• Journal: Cell (Cell) Vol. 184 Issue 2 Pg. 384-403.e21 (01 21 2021) ISSN: 1097-4172 [Electronic] United States
• PMID: 33450205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• MYC protein, human
• Proto-Oncogene Proteins c-myc
• RNA, Double-Stranded

Topics

• Adaptive Immunity (drug effects)
• Animals
• Antiviral Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cytoplasm (drug effects, metabolism)
• Female
• Gene Amplification (drug effects)
• Humans
• Immunity (drug effects)
• Introns (genetics)
• Mice
• Molecular Targeted Therapy
• Proto-Oncogene Proteins c-myc (metabolism)
• RNA Splicing (drug effects, genetics)
• RNA, Double-Stranded (metabolism)
• Signal Transduction (drug effects)
• Spliceosomes (drug effects, metabolism)
• Triple Negative Breast Neoplasms (genetics, immunology, pathology)