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

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Listed:
  • Adam E. Hall

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Sebastian Öther-Gee Pohl

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Patrizia Cammareri

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Stuart Aitken

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Nicholas T. Younger

    (University of Edinburgh)

  • Michela Raponi

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital
    Garscube Estate)

  • Caroline V. Billard

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Alfonso Bolado Carrancio

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Aslihan Bastem

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Paz Freile

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Fiona Haward

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital
    University of Dundee)

  • Ian R. Adams

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Javier F. Caceres

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Paula Preyzner

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Alex Kriegsheim

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Malcolm G. Dunlop

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Farhat V. Din

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

  • Kevin B. Myant

    (The University of Edinburgh, Western General Hospital Campus
    The University of Edinburgh, Western General Hospital)

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.

Suggested Citation

  • 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 & Fio, 2022. "RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30489-z
    DOI: 10.1038/s41467-022-30489-z
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    1. Agata N. Makar & Alina Boraman & Peter Mosen & Joanne E. Simpson & Jair Marques & Tim Michelberger & Stuart Aitken & Ann P. Wheeler & Dominic Winter & Alex Kriegsheim & Noor Gammoh, 2024. "The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.

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