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

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. SimonCalla 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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)384-403.e21
JournalCell
Volume184
Issue number2
DOIs
StatePublished - Jan 21 2021
Externally publishedYes

Keywords

  • anti-cancer immunity
  • antiviral immunity
  • double-stranded RNA
  • MYC
  • oncogenic stress
  • RNA splicing in cancer
  • spliceosome-targeted therapies
  • triple-negative breast cancer
  • viral mimicry

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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