TY - JOUR
T1 - RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer
AU - Hall, Adam E.
AU - Pohl, Sebastian Öther-gee
AU - Cammareri, Patrizia
AU - Aitken, Stuart
AU - Younger, Nicholas T.
AU - Raponi, Michela
AU - Billard, Caroline V.
AU - Carrancio, Alfonso Bolado
AU - Bastem, Aslihan
AU - Freile, Paz
AU - Haward, Fiona
AU - Adams, Ian R.
AU - Caceres, Javier F.
AU - Preyzner, Paula
AU - Von Kriegsheim, Alex
AU - Dunlop, Malcolm G.
AU - Din, Farhat V.
AU - Myant, Kevin B.
N1 - Funding Information:
This work was funded by Cancer Research UK (CRUK) under Career Development Fellowship, A19166 (K.B.M) and Small Molecule Drug Discovery Project Award, A25808 (K.B.M) and the European Research Council under Starting Grant, COLGENES – 715782 (K.B.M). Mass spectrometry was supported by the Wellcome Trust (Multiuser Equipment Grant 208402/Z/17/Z). We thank the University of Edinburgh’s Institute of Genetics and Cancer (IGC) technical staff for providing support for some of the experiments and we thank the animal technicians at the Biomedical Research Facility (BRF) facility for animal husbandry support. We thank Prof Owen Sansom for providing us with the VilCreERT2, Apcfl, P53fl, KrasG12Dand Lgr5-CreERT2 mouse lines. We thank Dr Lukas Dow and Prof Scott Lowe for providing the shApc organoid line. We thank Prof Nicola Valeri for providing the C-002 PDO line.
Funding Information:
This work was funded by Cancer Research UK (CRUK) under Career Development Fellowship, A19166 (K.B.M) and Small Molecule Drug Discovery Project Award, A25808 (K.B.M) and the European Research Council under Starting Grant, COLGENES – 715782 (K.B.M). Mass spectrometry was supported by the Wellcome Trust (Multiuser Equipment Grant 208402/Z/17/Z). We thank the University of Edinburgh’s Institute of Genetics and Cancer (IGC) technical staff for providing support for some of the experiments and we thank the animal technicians at the Biomedical Research Facility (BRF) facility for animal husbandry support. We thank Prof Owen Sansom for providing us with the VilCreERT2, Apc, P53, Kras and Lgr5-CreERT2 mouse lines. We thank Dr Lukas Dow and Prof Scott Lowe for providing the shApc organoid line. We thank Prof Nicola Valeri for providing the C-002 PDO line. fl fl G12D
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/5/19
Y1 - 2022/5/19
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-022-30489-z
DO - 10.1038/s41467-022-30489-z
M3 - Article
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
ER -