RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer

Adam E. Hall, Sebastian Öther-Gee Pohl, Patrizia Cammareri, Stuart Aitken, Nicholas T. Younger, Michela Raponi, Caroline V. Billard, Alfonso Bolado Carrancio, Aslihan Bastem, Paz Freile, Fiona Haward, Ian R. Adams, Javier F. Caceres, Paula Preyzner, Alex Kriegsheim, Malcolm G. Dunlop, Farhat V. Din and Kevin B. Myant ()
Additional contact information
Adam E. Hall: The University of Edinburgh, Western General Hospital Campus
Sebastian Öther-Gee Pohl: The University of Edinburgh, Western General Hospital Campus
Patrizia Cammareri: The University of Edinburgh, Western General Hospital Campus
Stuart Aitken: The University of Edinburgh, Western General Hospital Campus
Nicholas T. Younger: University of Edinburgh
Michela Raponi: The University of Edinburgh, Western General Hospital Campus
Caroline V. Billard: The University of Edinburgh, Western General Hospital Campus
Alfonso Bolado Carrancio: The University of Edinburgh, Western General Hospital Campus
Aslihan Bastem: The University of Edinburgh, Western General Hospital Campus
Paz Freile: The University of Edinburgh, Western General Hospital Campus
Fiona Haward: The University of Edinburgh, Western General Hospital Campus
Ian R. Adams: The University of Edinburgh, Western General Hospital Campus
Javier F. Caceres: The University of Edinburgh, Western General Hospital Campus
Paula Preyzner: The University of Edinburgh, Western General Hospital Campus
Alex Kriegsheim: The University of Edinburgh, Western General Hospital Campus
Malcolm G. Dunlop: The University of Edinburgh, Western General Hospital Campus
Farhat V. Din: The University of Edinburgh, Western General Hospital Campus
Kevin B. Myant: The University of Edinburgh, Western General Hospital Campus

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Tumour cell plasticity is a major barrier to the efficacy of targeted cancer therapies but the mechanisms that mediate it are poorly understood. Here, we identify dysregulated RNA splicing as a key driver of tumour cell dedifferentiation in colorectal cancer (CRC). We find that Apc-deficient CRC cells have dysregulated RNA splicing machinery and exhibit global rewiring of RNA splicing. We show that the splicing factor SRSF1 controls the plasticity of tumour cells by controlling Kras splicing and is required for CRC invasion in a mouse model of carcinogenesis. SRSF1 expression maintains stemness in human CRC organoids and correlates with cancer stem cell marker expression in human tumours. Crucially, partial genetic downregulation of Srsf1 does not detrimentally affect normal tissue homeostasis, demonstrating that tumour cell plasticity can be differentially targeted. Thus, our findings link dysregulation of the RNA splicing machinery and control of tumour cell plasticity.

Date: 2022
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DOI: 10.1038/s41467-022-30489-z

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