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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells

Published on: April 26, 2017

Steering research on mRNA splicing in cancer towards clinical translation

Olga Anczukow¹, Frédéric H-T Allain², Brittany L Angarola³

¹The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA. olga.anczukow@jax.org.

Nature Reviews. Cancer

|October 9, 2024

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.

Insights

Dysregulated mRNA splicing is common in cancers, offering new therapeutic targets. Understanding these splicing aberrations is key to developing novel cancer treatments and improving patient outcomes.

Area of Science:

Oncology
Molecular Biology
Genetics

Background:

Somatic mutations and copy number variations affecting splicing factors are observed in various cancers.
Spliceosome components have dual roles, participating in DNA repair and other cellular processes, complicating their direct role in cancer initiation.
Dysregulated mRNA splicing is a widespread hallmark of most cancers, presenting potential therapeutic vulnerabilities.

Purpose of the Study:

To highlight the significance of mRNA splicing aberrations in cancer.
To discuss the challenges and opportunities in translating splicing research into clinical applications.
To explore novel therapeutic strategies targeting cancer-specific splicing alterations.

Main Methods:

Review of current literature on splicing factor mutations in malignancies.
Analysis of technological limitations in RNA sequencing for isoform resolution.
Discussion of potential therapeutic approaches including small-molecule inhibitors and immunotherapy.

Main Results:

Widespread splicing alterations, not just individual isoforms, may be a crucial feature of human cancers.
Current sequencing technologies face limitations in fully defining the landscape of splicing aberrations.
Several therapeutic avenues are proposed, including targeting splicing aberrations directly or indirectly.

Conclusions:

Interpreting splicing aberrations in cancer can reveal novel tumor vulnerabilities and therapeutic opportunities.
Overcoming technological and conceptual challenges is crucial for clinical translation of splicing-based cancer therapies.
Targeting splicing dysregulation offers promising avenues for novel cancer treatment strategies.

Read full analysis

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