The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer
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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.
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Metadata
- Authors
- Bowling, E. A., Wang, J. H., Gong, F., Wu, W., Neill, N. J., Kim, I. S., Tyagi, S., Orellana, M., Kurley, S. J., Dominguez-Vidaña, R., Chung, H.-C., Hsu, T. Y.-T., Dubrulle, J., Saltzman, A. B., Li, H., Meena, J. K., Canlas, G. M., Chamakuri, S., Singh, S., Simon, L. M., Olson, C. M., Dobrolecki, L. E., Lewis, M. T., Zhang, B., Golding, I., Rosen, J. M., Young, D. W., Malovannaya, A., Stossi, F., Miles, G., Ellis, M. J., Yu, L., Buonamici, S., Lin, C. Y., Karlin, K. L., Zhang, X. H.-F., & Westbrook, T. F.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 184
- Issue
- 2
- Pages
- 384-403.e21
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W3119554079
- Cited by
- 224
- References
- 32
- FWCI
- 10.73
- Type
- journal article
- Language
- en
- Open access
- bronze
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