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 Von Kriegsheim, Malcolm G. Dunlop, Farhat V. Din, Kevin B. Myant

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalNature Communications
Volume13
Issue number1
Early online date19 May 2022
DOIs
Publication statusE-pub ahead of print - 19 May 2022

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