Steering Research on mRNA Splicing in Cancer Towards Clinical Translation

Authors

Olga Anczukow
Frédéric H-T Allain
Brittany L Angarola
Douglas L Black
Angela N Brooks
Chonghui Cheng
Ana Conesa
Edie I Crosse
Eduardo Eyras
Ernesto Guccione
Sydney X Lu
Karla M Neugebauer
Priyanka Sehgal
Xiao Song
Zuzana Tothova
Juan Valcárcel
Kevin M Weeks
Gene W Yeo
Andrei Thomas-Tikhonenko

Publication Date

12-1-2024

Journal

Nature Reviews Cancer

DOI

10.1038/s41568-024-00750-2

PMID

39384951

PMCID

PMC11698124

PubMedCentral® Posted Date

1-3-2025

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

no

Keywords

Humans, Neoplasms, RNA Splicing, RNA, Messenger, Spliceosomes, Translational Research, Biomedical

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.