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 (Lead / Corresponding author)

School of Life Sciences

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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
Number of pages	19
Journal	Nature Communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-022-30489-z
Publication status	Published - 19 May 2022

Keywords

Animals
Carcinogenesis/genetics
Cell Plasticity/genetics
Colorectal Neoplasms/pathology
Gene Expression Regulation, Neoplastic
Mice
RNA Splicing/genetics
Serine-Arginine Splicing Factors/genetics

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-022-30489-zLicence: CC BY

Final Published VersionFinal published version, 10.4 MBLicence: CC BY

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Hall, A. E., Pohl, S. Ö.-G., 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, Article 2791. https://doi.org/10.1038/s41467-022-30489-z

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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.",

keywords = "Animals, Carcinogenesis/genetics, Cell Plasticity/genetics, Colorectal Neoplasms/pathology, Gene Expression Regulation, Neoplastic, Mice, RNA Splicing/genetics, Serine-Arginine Splicing Factors/genetics",

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). {\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",

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Hall, AE, Pohl, SÖ-G, 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, 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). © 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.

KW - Animals

KW - Carcinogenesis/genetics

KW - Cell Plasticity/genetics

KW - Colorectal Neoplasms/pathology

KW - Gene Expression Regulation, Neoplastic

KW - Mice

KW - RNA Splicing/genetics

KW - Serine-Arginine Splicing Factors/genetics

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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

M1 - 2791

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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