Spliceosome-Targeted Therapies Trigger an Antiviral Immune Response in Triple-Negative Breast Cancer
Publication Date
1-21-2021
Journal
Cell
DOI
10.1016/j.cell.2020.12.031
PMID
33450205
PMCID
PMC8635244
PubMedCentral® Posted Date
1-21-2022
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Adaptive Immunity, Animals, Antiviral Agents, Apoptosis, Cell Line, Tumor, Cytoplasm, Female, Gene Amplification, Humans, Immunity, Introns, Mice, Molecular Targeted Therapy, Proto-Oncogene Proteins c-myc, RNA Splicing, RNA, Double-Stranded, Signal Transduction, Spliceosomes, Triple Negative Breast Neoplasms
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.
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