Cargando…
RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer
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 cel...
Autores principales: | , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120198/ https://www.ncbi.nlm.nih.gov/pubmed/35589755 http://dx.doi.org/10.1038/s41467-022-30489-z |
_version_ | 1784710884699930624 |
---|---|
author | Hall, Adam E. Pohl, Sebastian Öther-Gee Cammareri, Patrizia Aitken, Stuart Younger, Nicholas T. Raponi, Michela Billard, Caroline V. Carrancio, Alfonso Bolado Bastem, Aslihan Freile, Paz Haward, Fiona Adams, Ian R. Caceres, Javier F. Preyzner, Paula von Kriegsheim, Alex Dunlop, Malcolm G. Din, Farhat V. Myant, Kevin B. |
author_facet | Hall, Adam E. Pohl, Sebastian Öther-Gee Cammareri, Patrizia Aitken, Stuart Younger, Nicholas T. Raponi, Michela Billard, Caroline V. Carrancio, Alfonso Bolado Bastem, Aslihan Freile, Paz Haward, Fiona Adams, Ian R. Caceres, Javier F. Preyzner, Paula von Kriegsheim, Alex Dunlop, Malcolm G. Din, Farhat V. Myant, Kevin B. |
author_sort | Hall, Adam E. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9120198 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-91201982022-05-21 RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer Hall, Adam E. Pohl, Sebastian Öther-Gee Cammareri, Patrizia Aitken, Stuart Younger, Nicholas T. Raponi, Michela Billard, Caroline V. Carrancio, Alfonso Bolado Bastem, Aslihan Freile, Paz Haward, Fiona Adams, Ian R. Caceres, Javier F. Preyzner, Paula von Kriegsheim, Alex Dunlop, Malcolm G. Din, Farhat V. Myant, Kevin B. Nat Commun Article 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. Nature Publishing Group UK 2022-05-19 /pmc/articles/PMC9120198/ /pubmed/35589755 http://dx.doi.org/10.1038/s41467-022-30489-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Hall, Adam E. Pohl, Sebastian Öther-Gee Cammareri, Patrizia Aitken, Stuart Younger, Nicholas T. Raponi, Michela Billard, Caroline V. Carrancio, Alfonso Bolado Bastem, Aslihan Freile, Paz Haward, Fiona Adams, Ian R. Caceres, Javier F. Preyzner, Paula von Kriegsheim, Alex Dunlop, Malcolm G. Din, Farhat V. Myant, Kevin B. RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer |
title | RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer |
title_full | RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer |
title_fullStr | RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer |
title_full_unstemmed | RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer |
title_short | RNA splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer |
title_sort | rna splicing is a key mediator of tumour cell plasticity and a therapeutic vulnerability in colorectal cancer |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120198/ https://www.ncbi.nlm.nih.gov/pubmed/35589755 http://dx.doi.org/10.1038/s41467-022-30489-z |
work_keys_str_mv | AT halladame rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT pohlsebastianothergee rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT cammareripatrizia rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT aitkenstuart rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT youngernicholast rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT raponimichela rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT billardcarolinev rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT carrancioalfonsobolado rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT bastemaslihan rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT freilepaz rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT hawardfiona rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT adamsianr rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT caceresjavierf rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT preyznerpaula rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT vonkriegsheimalex rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT dunlopmalcolmg rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT dinfarhatv rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer AT myantkevinb rnasplicingisakeymediatoroftumourcellplasticityandatherapeuticvulnerabilityincolorectalcancer |