An SRRM3-regulated neural alternative splicing program is subverted to promote tumor progression in pancreatic neuroendocrine cells.

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of neoplasms arising in pancreatic islets and altering the hormone-secreting function of neuroendocrine cells. Genome-wide approaches have revealed the genomic landscape of PanNETs but have not explained their problematic hormone secretion. We show here that alternative splicing (AS) deregulation is responsible for changes in the secretory ability of PanNET cells. We reveal that the RNA-binding protein SRRM3 is upregulated in PanNETs and favors the inclusion of a group of alternative microexons in certain mRNAs. These microexons are part of a larger neural program regulated by SRRM3, and their inclusion results in protein isoforms that change stimulus-induced insulin trafficking and secretion. By downregulating SRRM3 or inhibiting its binding to three of the microexon-bearing pre-mRNAs in animal and cellular PanNET models, we prove the necessity of SRRM3 for hormone secretion, PanNET progression, and enhancement of the neural component of PanNET tumors.