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

被引：20

作者：

Hall, Adam E. ^{[1
,2
]}

Pohl, Sebastian Other-Gee ^{[1
,2
]}

Cammareri, Patrizia ^{[1
,2
]}

Aitken, Stuart ^{[1
,3
]}

Younger, Nicholas T. ^{[4
]}

Raponi, Michela ^{[1
,2
,5
]}

Billard, Caroline V. ^{[1
,2
]}

Carrancio, Alfonso Bolado ^{[1
,2
]}

Bastem, Aslihan ^{[1
,2
]}

Freile, Paz ^{[1
,2
]}

Haward, Fiona ^{[1
,3
,6
]}

Adams, Ian R. ^{[1
,3
]}

Caceres, Javier F. ^{[1
,3
]}

Preyzner, Paula ^{[1
,2
]}

von Kriegsheim, Alex ^{[1
,2
]}

Dunlop, Malcolm G. ^{[1
,3
]}

Din, Farhat V. ^{[1
,2
]}

Myant, Kevin B. ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Inst Genet & Canc, Western Gen Hosp Campus,Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland

[2] Univ Edinburgh, Inst Genet & Canc, Western Gen Hosp, Canc Res UK Edinburgh Ctr, Crewe Rd South, Edinburgh EH4 2XR, Midlothian, Scotland

[3] Univ Edinburgh, Inst Genet & Canc, Western Gen Hosp, MRC Human Genet Unit, Crewe Rd, Edinburgh EH4 2XU, Midlothian, Scotland

[4] Univ Edinburgh, Ctr Inflammat Res, Edinburgh EH16 4TJ, Midlothian, Scotland

[5] Canc Res UK Beatson Inst, Garscube Estate,Switchback Rd, Glasgow G61 1BD, Lanark, Scotland

[6] Univ Dundee, Sch Life Sci, Ctr Gene Regulat & Express, Dow St, Dundee DD1 5EH, Scotland

来源：

NATURE COMMUNICATIONS | 2022年 / 13卷 / 01期

基金：

英国惠康基金; 欧洲研究理事会;

关键词：

STEM-CELLS; SMALL-INTESTINE; COLON; ACTIVATION; MODEL; WNT; DEDIFFERENTIATION; MICROENVIRONMENT; QUANTIFICATION; IDENTIFICATION;

D O I：

10.1038/s41467-022-30489-z

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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. The influence of mRNA splicing on colon cancer development and progression is unclear. In this study, the authors demonstrate that the SRSF1 splicing factor is essential to sustain the stem cell phenotype of WNT-activated colorectal cancers.

引用

页数：19

共 78 条

[1] SRSF1-Regulated Alternative Splicing in Breast Cancer [J].