Steering research on mRNA splicing in cancer towards clinical translation.

Autor: Anczukow O; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. olga.anczukow@jax.org., Allain FH; Department of Biology, Eidgenössische Technische Hochschule (ETH), Zürich, Switzerland., Angarola BL; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA., Black DL; Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA., Brooks AN; Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA., Cheng C; Department of Molecular and Human Genetics, Lester & Sue Breast Center, Baylor College of Medicine, Houston, TX, USA., Conesa A; Institute for Integrative Systems Biology, Spanish National Research Council, Paterna, Spain., Crosse EI; Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA., Eyras E; Shine-Dalgarno Centre for RNA Innovation, Australian National University, Canberra, Australian Capital Territory, Australia., Guccione E; Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, USA., Lu SX; Department of Medicine, Stanford Medical School, Palo Alto, CA, USA., Neugebauer KM; Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT, USA., Sehgal P; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA., Song X; Department of Neurology, Northwestern University, Chicago, IL, USA., Tothova Z; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Valcárcel J; Centre for Genomic Regulation, Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain., Weeks KM; Department of Chemistry, University of North Carolina, Chapel Hill, NC, USA., Yeo GW; Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA., Thomas-Tikhonenko A; Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. andreit@pennmedicine.upenn.edu.; Department of Pathology & Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA. andreit@pennmedicine.upenn.edu.
Jazyk: angličtina
Zdroj: Nature reviews. Cancer [Nat Rev Cancer] 2024 Dec; Vol. 24 (12), pp. 887-905. Date of Electronic Publication: 2024 Oct 09.
DOI: 10.1038/s41568-024-00750-2
Abstrakt: 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.
Competing Interests: Competing interests: J.V. is a member of the Advisory Boards of Remix Therapeutics, Stoke Therapeutics and IntronX. K.M.W. is an adviser to and holds equity in Ribometrix, ForagR Medicines and A-Form Solutions. O.A. is a member of the Advisory Boards of Caeruleus Genomics.
(© 2024. Springer Nature Limited.)
Databáze: MEDLINE
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