RBFOX2 modulates a metastatic signature of alternative splicing in pancreatic cancer

Amina Jbara, Kuan-Ting Lin, Chani Stossel, Zahava Siegfried, Haya Shqerat, Adi Amar-Schwartz, Ela Elyada, Maxim Mogilevsky, Maria Raitses-Gurevich, Jared L. Johnson, Tomer M. Yaron, Ofek Ovadia, Gun Ho Jang, Miri Danan-Gotthold, Lewis C. Cantley, Erez Y. Levanon, Steven Gallinger, Adrian R. Krainer, Talia Golan and Rotem Karni ()
Additional contact information
Amina Jbara: Hebrew University–Hadassah Medical School
Kuan-Ting Lin: Cold Spring Harbor Laboratory
Chani Stossel: Sheba Medical Center Tel Hashomer
Zahava Siegfried: Hebrew University–Hadassah Medical School
Haya Shqerat: Hebrew University–Hadassah Medical School
Adi Amar-Schwartz: Hebrew University–Hadassah Medical School
Ela Elyada: Hebrew University–Hadassah Medical School
Maxim Mogilevsky: Hebrew University–Hadassah Medical School
Maria Raitses-Gurevich: Sheba Medical Center Tel Hashomer
Jared L. Johnson: Weill Cornell Medicine
Tomer M. Yaron: Weill Cornell Medicine
Ofek Ovadia: Hebrew University–Hadassah Medical School
Gun Ho Jang: University of Toronto
Miri Danan-Gotthold: Bar-Ilan University
Lewis C. Cantley: Weill Cornell Medicine
Erez Y. Levanon: Bar-Ilan University
Steven Gallinger: University of Toronto
Adrian R. Krainer: Cold Spring Harbor Laboratory
Talia Golan: Sheba Medical Center Tel Hashomer
Rotem Karni: Hebrew University–Hadassah Medical School

Nature, 2023, vol. 617, issue 7959, 147-153

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05820-3

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