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...

Full description

Saved in:

Bibliographic Details
Published in:	Nature communications 2022-05, Vol.13 (1), p.2791-19, Article 2791
Main Authors:	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
Format:	Article
Language:	eng
Subjects:	Adenomatous polyposis coli Adenomatous polyposis coli protein Animals Carcinogenesis Carcinogenesis - genetics Carcinogenesis - metabolism Carcinogens Cell Plasticity - genetics Colon Colon cancer Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - pathology Gene Expression Regulation, Neoplastic Homeostasis Machinery Mice mRNA Organoids Phenotypes Plastic properties Plasticity Ribonucleic acid RNA RNA Splicing - genetics Serine-Arginine Splicing Factors - genetics Serine-Arginine Splicing Factors - metabolism Splicing Splicing factors Stem cells Tumors Wnt protein
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	2041-1723 2041-1723