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.
|Number of pages||7|
|Early online date||22 Mar 2023|
|State||Published - 4 May 2023|
Bibliographical noteFunding Information:
The authors thank S. Winograd-Katz and B. Geiger for fruitful discussions; Y. Cohen, A. Mogilevsky, A. Prabhu and A. Elhaj for assistance with in vitro and in vivo experiment validations. The authors also acknowledge support for A.J. from the Israel Ministry of Science, Zvi Yanai Ph.D. and post-doctoral fellowship programme for outstanding minority students. This research study was further supported by the Alex U. Soyka Pancreatic Cancer Research grant (CFHU), the Israel Cancer Association grant number 20220038, ISF grant 1510/17 (to R.K.) and Binational Science Foundation (BSF) grant number 2021108 (to R.K. and A.R.K.). K.-T.L. and A.R.K. acknowledge support provided by the NCI grant CA13106.
© 2023, The Author(s).