Taken together, these data demonstrate RBFOX2 primarily mediates alternative splicing of a subset of exons in pancreatic cancer involved in cytoskeletal remodeling through RAC1 downstream targets, and this splicing is driven by RBFOX2 nuclear abundance, with variable RBFOX2 expression and PSI values for target exons observed across cell lines and patient samples. Here, RBFOX2 is linked to familial pancreatic carcinoma.