Steering research on mRNA splicing in cancer towards clinical translation.
Document Type
Article
Publication Date
12-1-2024
Original Citation
Anczuków O,
Allain F,
Angarola B,
Black D,
Brooks A,
Cheng C,
Conesa A,
Crosse E,
Eyras E,
Guccione E,
Lu S,
Neugebauer K,
Sehgal P,
Song X,
Tothova Z,
Valcárcel J,
Weeks K,
Yeo G,
Thomas-Tikhonenko A.
Steering research on mRNA splicing in cancer towards clinical translation. Nat Rev Cancer. 2024;24(12):887-905.
Keywords
JGM, Humans, Neoplasms, RNA Splicing, RNA, Messenger, Spliceosomes, Translational Research, Biomedical
JAX Source
Nat Rev Cancer. 2024;24(12):887-905.
ISSN
1474-1768
PMID
39384951
DOI
https://doi.org/10.1038/s41568-024-00750-2
Grant
The authors thank the Forbeck Foundation for supporting the Forbeck Forum on Therapeutic Targeting of mRNA Splicing in Cancer (co-chairs: A.T.-T. and O.A.). Relevant research in the authors’ laboratories was supported by National Institutes of Health (NIH) grants (, R21AG080243 and P30CA034196 to O.A).Scott R. MacKenzie Foundation Grant (to O.A.),
Abstract
Splicing factors are affected by recurrent somatic mutations and copy number variations in several types of haematologic and solid malignancies, which is often seen as prima facie evidence that splicing aberrations can drive cancer initiation and progression. However, numerous spliceosome components also 'moonlight' in DNA repair and other cellular processes, making their precise role in cancer difficult to pinpoint. Still, few would deny that dysregulated mRNA splicing is a pervasive feature of most cancers. Correctly interpreting these molecular fingerprints can reveal novel tumour vulnerabilities and untapped therapeutic opportunities. Yet multiple technological challenges, lingering misconceptions, and outstanding questions hinder clinical translation. To start with, the general landscape of splicing aberrations in cancer is not well defined, due to limitations of short-read RNA sequencing not adept at resolving complete mRNA isoforms, as well as the shallow read depth inherent in long-read RNA-sequencing, especially at single-cell level. Although individual cancer-associated isoforms are known to contribute to cancer progression, widespread splicing alterations could be an equally important and, perhaps, more readily actionable feature of human cancers. This is to say that in addition to 'repairing' mis-spliced transcripts, possible therapeutic avenues include exacerbating splicing aberration with small-molecule spliceosome inhibitors, targeting recurrent splicing aberrations with synthetic lethal approaches, and training the immune system to recognize splicing-derived neoantigens.