RNA splicing is an important biological process associated with cancer initiation and progression, yet in pancreatic cancer the role and regulation of splicing is not well understood. From a forward genetic screen in a mouse model of pancreatic cancer, we identified an enrichment of RNA binding proteins (RBPs) associated with the spliceosome. Here, we link deregulation of RBFOX2, an RBP of the FOX family, to pancreatic cancer progression and liver metastasis. We show that RBFOX2 regulation in

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... ncreatic cancer occurs at both the RNA and protein level, and that nuclear localization of RBFOX2 is significantly reduced in poorly differentiated PDAC. Deregulation of RBFOX2 in PDAC is associated with an enrichment of exon exclusion events in transcripts encoding proteins involved in cytoskeletal remodeling and invadopodia programs that potentiate metastatic potential in vivo. Using splice-switching antisense oligonucleotides (AONs) and inducible cDNA isoforms, we demonstrate that RBFOX2 mediated exon exclusion in ABI1 controls the abundance and localization of ABI1 protein isoforms in pancreatic cancer cells, and that ABI1 splice-switching enhances cellular phenotypes associated with cancer cell stemness. Together, our data identify a novel role for RBFOX2 deregulation in promoting PDAC progression through alternative splicing regulation.