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

Area of Science:

• Molecular Biology
• Oncology
• Genetics

Background:

• Pancreatic neuroendocrine tumors (PanNETs) are complex neoplasms affecting neuroendocrine cell hormone secretion.
• Previous genomic studies have not fully elucidated the mechanisms behind PanNETs' aberrant hormone secretion.
• Alternative splicing (AS) is a key regulator of gene expression with implications in cancer.

Purpose of the Study:

• To investigate the role of alternative splicing deregulation in PanNETs' secretory dysfunction.
• To identify specific RNA-binding proteins and their targets involved in PanNET hormone secretion.
• To explore therapeutic strategies targeting AS pathways in PanNETs.

Main Methods:

• Analysis of RNA-binding protein expression in PanNETs.
• Identification of SRRM3-regulated alternative microexons in PanNET cells.
• Functional studies in cellular and animal PanNET models involving SRRM3 downregulation and inhibition of its mRNA binding.

Main Results:

• SRRM3 is upregulated in PanNETs and promotes the inclusion of specific microexons in target mRNAs.
• Inclusion of these microexons generates protein isoforms that alter stimulus-induced insulin trafficking and secretion.
• Downregulation of SRRM3 or inhibition of its binding to microexon-containing pre-mRNAs reduces hormone secretion, inhibits PanNET progression, and diminishes the neural phenotype.

Conclusions:

• Alternative splicing deregulation, particularly SRRM3-mediated microexon inclusion, is a critical driver of secretory changes in PanNETs.
• SRRM3 plays a necessary role in PanNET hormone secretion, tumor progression, and the enhancement of their neural component.
• Targeting SRRM3 represents a potential therapeutic avenue for managing PanNETs.