Dysregulation of RNA splicing linked to tumour cell plasticity
Edinburgh researchers show that RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer: August 2022
Tumour cell plasticity can be defined as the ability of cancer cells to change their characteristics in response to environmental cues. It often contributes to tumours acquiring resistance to anticancer therapeutics. Unfortunately, the mechanisms that mediate tumour cell plasticity are still poorly understood.
Exploring mechanisms of colorectal carcinogenesis using animal models and patient-derived colorectal cancer organoid models, our investigators discovered that cancers in which the tumour suppressor gene APC has been deleted display striking changes in RNA splicing (a process of transforming newly-made precursor messenger RNA transcripts into a mature messenger RNA). Inactivation of APC gene by mutation or deletion - leading to hyperactivation of the so called Wnt signalling pathway (an ancient and evolutionarily conserved pathway that regulates crucial aspects of cell behaviour) - has been reported in ~80% of all human colon tumours, so this discovery was very intriguing. Their experiments also showed that multiple genes involved in RNA splicing were upregulated, suggesting that there may be an increased requirement for RNA splicing during colorectal cancer development and progression. Subsequent studies confirmed that inhibition of RNA splicing reduced viability and growth of cancerous cells. It also reduced the ability of cancer cells to dedifferentiate and acquire stem-cell-like characteristics causing decreased plasticity of these cells. The researchers identified the splicing factor SRSF1, the archetype member of the serine and arginine-rich (SR) protein family of splicing regulators, as an important controller of stemness and plasticity of tumour cells. SRSF1 potential to regulate plasticity of cancer cells results, at least in part, from its ability to control splicing of the oncogene K-ras. Crucially, cancer cells seem to be much more dependent on SRSF1 function than non-cancerous tissue, indicating that RNA splicing machinery components (and SRSF1 in particular) might represent interesting targets for development of future cancer therapeutics.
The work, titled "RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer", was published in the journal Nature Communications. It was led by Dr Kevin Myant and supported by funding from Cancer Research UK, European Research Council and the Wellcome Trust.
Our experiments showed that targeting SRSF1 can impair cancer progression in laboratory models of colorectal cancer. The study defines SRSF1 as an important regulator of tumour cell plasticity and indicates that it could represent a valid therapeutic target. We are hopeful that this research could pave the way to development of better cancer treatments in the future.
Article in Nature Communications: https://www.nature.com/articles/s41467-022-30489-z
Doctor Kevin Myant Group website: https://www.ed.ac.uk/cancer-centre/research/myant-group
Information about bowel cancer: https://www.cancerresearchuk.org/about-cancer/bowel-cancer
Interesting presentation about RNA splicing: https://www.youtube.com/watch?v=53v2u9ukCt0