RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer

Jbara, Amina, Lin, Kuan-Ting, Stossel, Chani, Siegfried, Zahava, Shqerat, Haya, Amar-Schwartz, Adi, Elyada, Ela, Mogilevsky, Maxim, Raitses-Gurevich, Maria, Johnson, Jared L, Yaron, Tomer M, Ovadia, Ofek, Jang, Gun Ho, Danan-Gotthold, Miri, Cantley, Lewis C, Levanon, Erez Y, Gallinger, Steven, Krainer, Adrian R, Golan, Talia, Karni, Rotem (May 2023) RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer. Nature, 617 (7959). pp. 147-153. ISSN 0028-0836 (Public Dataset)

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Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by aggressive local invasion and metastatic spread, leading to high lethality. Although driver gene mutations during PDA progression are conserved, no specific mutation is correlated with the dissemination of metastases1-3. Here we analysed RNA splicing data of a large cohort of primary and metastatic PDA tumours to identify differentially spliced events that correlate with PDA progression. De novo motif analysis of these events detected enrichment of motifs with high similarity to the RBFOX2 motif. Overexpression of RBFOX2 in a patient-derived xenograft (PDX) metastatic PDA cell line drastically reduced the metastatic potential of these cells in vitro and in vivo, whereas depletion of RBFOX2 in primary pancreatic tumour cell lines increased the metastatic potential of these cells. These findings support the role of RBFOX2 as a potent metastatic suppressor in PDA. RNA-sequencing and splicing analysis of RBFOX2 target genes revealed enrichment of genes in the RHO GTPase pathways, suggesting a role of RBFOX2 splicing activity in cytoskeletal organization and focal adhesion formation. Modulation of RBFOX2-regulated splicing events, such as via myosin phosphatase RHO-interacting protein (MPRIP), is associated with PDA metastases, altered cytoskeletal organization and the induction of focal adhesion formation. Our results implicate the splicing-regulatory function of RBFOX2 as a tumour suppressor in PDA and suggest a therapeutic approach for metastatic PDA.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > Alternative Splicing organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions diseases & disorders > cancer > metastasis organs, tissues, organelles, cell types and functions diseases & disorders > cancer > cancer types > pancreatic cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor diseases & disorders > cancer > cancer types
CSHL Authors:	Lin, Kuan-Ting Krainer, Adrian R.
Communities:	CSHL labs > Krainer lab CSHL Cancer Center Program CSHL Cancer Center Program > Gene Regulation and Inheritance Program CSHL Cancer Center Shared Resources > Sequencing Technology & Analysis Service
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	May 2023
Date Deposited:	29 Sep 2023 15:40
Last Modified:	09 Feb 2024 14:43
PMCID:	PMC10156590
Related URLs:	Publisher
Dataset ID:	BioProject: PRJNA797585
URI:	https://repository.cshl.edu/id/eprint/41060

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