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

doi:10.1038/s41467-022-30489-z

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 journal › Article › peer-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 language	English
Article number	2791
Journal	Nature Communications
Volume	13
Issue number	1
Early online date	19 May 2022
DOIs	https://doi.org/10.1038/s41467-022-30489-z
Publication status	Published - 19 May 2022

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RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer_finalFinal published version, 10.4 MB

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Maintaining Genetic and Chromosomal Stability in the Mammalian Germline
Adams, I. (Principal Investigator)
1/04/18 → 31/03/23
Project: Research
Target validation of the RNA splicing factor SRSF1
Din, F. (Principal Investigator) & Myant, K. (Co-investigator)
UK-based charities
1/02/18 → 31/05/21
Project: Research
High resolution metabolite and peptide mass spectrometry
Von Kriegsheim, A. (Principal Investigator), Christophorou, M. (Co-investigator), Finch, A. (Co-investigator), Morton, N. (Co-investigator), Ponting, C. (Co-investigator) & Walmsley, S. (Co-investigator)
UK-based charities
2/10/17 → 1/11/22
Project: Research

Institute for Genetics and Cancer Mass Spectrometry Facility
Von Kriegsheim, A. (Manager)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

Hall, A. E., Pohl, S. Ö., Cammareri, P., Aitken, S., Younger, N. T., Raponi, M., Billard, C. V., Carrancio, A. B., Bastem, A., Freile, P., Haward, F., Adams, I. R., Caceres, J. F., Preyzner, P., Von Kriegsheim, A., Dunlop, M. G., Din, F. V., & Myant, K. B. (2022). RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer. Nature Communications, 13(1), Article 2791. https://doi.org/10.1038/s41467-022-30489-z

@article{2f95a2bc898d4dde971376ea12066b92,

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

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. ",

author = "Hall, {Adam E.} and Pohl, {Sebastian {\"O}ther-gee} and Patrizia Cammareri and Stuart Aitken and Younger, {Nicholas T.} and Michela Raponi and Billard, {Caroline V.} and Carrancio, {Alfonso Bolado} and Aslihan Bastem and Paz Freile and Fiona Haward and Adams, {Ian R.} and Caceres, {Javier F.} and Paula Preyzner and {Von Kriegsheim}, Alex and Dunlop, {Malcolm G.} and Din, {Farhat V.} and Myant, {Kevin B.}",

note = "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{\textquoteright}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{\textquoteright}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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = may,

day = "19",

doi = "10.1038/s41467-022-30489-z",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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Hall, AE, Pohl, SÖ , Cammareri, P, Aitken, S, Younger, NT, Raponi, M, Billard, CV, Carrancio, AB, Bastem, A, Freile, P, Haward, F, Adams, IR , Caceres, JF, Preyzner, P, Von Kriegsheim, A , Dunlop, MG , Din, FV & Myant, KB 2022, 'RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer', Nature Communications, vol. 13, no. 1, 2791. https://doi.org/10.1038/s41467-022-30489-z

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

C2 - 35589755

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2791

ER -

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

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Projects

Maintaining Genetic and Chromosomal Stability in the Mammalian Germline

Target validation of the RNA splicing factor SRSF1

High resolution metabolite and peptide mass spectrometry

Equipment

Institute for Genetics and Cancer Mass Spectrometry Facility

Cite this