RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing

Michelle Maurin, Mohammadreza Ranjouri, Cristina Megino-Luque, Justin Y. Newberg, Dongliang Du, Katelyn Martin, Robert E. Miner, Mollie S. Prater, Dave Keng Boon Wee, Barbara Centeno, Shondra M. Pruett-Miller, Paul Stewart, Jason B. Fleming, Xiaoqing Yu, Jose Javier Bravo-Cordero, Ernesto Guccione, Michael A. Black and Karen M. Mann ()
Additional contact information
Michelle Maurin: Moffitt Cancer Center
Mohammadreza Ranjouri: Moffitt Cancer Center
Cristina Megino-Luque: Icahn School of Medicine at Mount Sinai
Justin Y. Newberg: Moffitt Cancer Center
Dongliang Du: Moffitt Cancer Center
Katelyn Martin: Moffitt Cancer Center
Robert E. Miner: Moffitt Cancer Center
Mollie S. Prater: St. Jude Children’s Research Hospital
Dave Keng Boon Wee: Technology and Research (A*STAR)
Barbara Centeno: Moffitt Cancer Center
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Paul Stewart: Moffitt Cancer Center
Jason B. Fleming: Moffitt Cancer Center
Xiaoqing Yu: Moffitt Cancer Center
Jose Javier Bravo-Cordero: Icahn School of Medicine at Mount Sinai
Ernesto Guccione: Icahn School of Medicine at Mount Sinai
Michael A. Black: University of Otago
Karen M. Mann: Moffitt Cancer Center

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract RNA splicing is an important biological process associated with cancer initiation and progression. However, the contribution of alternative splicing to pancreatic cancer (PDAC) development is not well understood. Here, we identify an enrichment of RNA binding proteins (RBPs) involved in splicing regulation linked to PDAC progression from a forward genetic screen using Sleeping Beauty insertional mutagenesis in a mouse model of pancreatic cancer. We demonstrate downregulation of RBFOX2, an RBP of the FOX family, promotes pancreatic cancer progression and liver metastasis. Specifically, we show RBFOX2 regulates exon splicing events in transcripts encoding proteins involved in cytoskeletal remodeling programs. These exons are differentially spliced in PDAC patients, with enhanced exon skipping in the classical subtype for several RBFOX2 targets. RBFOX2 mediated splicing of ABI1, encoding the Abelson-interactor 1 adapter protein, controls the abundance and localization of ABI1 protein isoforms in pancreatic cancer cells and promotes the relocalization of ABI1 from the cytoplasm to the periphery of migrating cells. Using splice-switching antisense oligonucleotides (AONs) we demonstrate the ABI1 ∆Ex9 isoform enhances cell migration. Together, our data identify a role for RBFOX2 in promoting PDAC progression through alternative splicing regulation.

Date: 2023
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DOI: 10.1038/s41467-023-44126-w

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