Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability

Pseudomyxoma peritonei (PMP) is a rare neoplasm coursing with uncontrollable mucus accumulation, with a high relapse rate. RNA biology processes have emerged as new players in cancer development and progression, nevertheless their role in PMP remains unknown. In this study, we aimed to examine RNA-regulatory machineries in PMP and their potential contribution to this disease progression. We analyzed 62 splicing-related genes, 27 RNA exosome and 21 nonsense-mediated decay genes, in a cohort of 29 patients using a microfluidic array, comparing tumor and control/reference tissues, together with external RNA-seq and proteomic data. Our results revealed a profound dysregulation of key components, which correlated to relevant clinical parameters and enabled to distinguish between tumor and control tissues. In vitro splicing inhibition using Pladienolide-B, as well as the modulation of specific splicing factors, reduced aggressiveness parameters, enhanced the effect of clinically used drugs, and revealed a strong correlation between dysregulated genes and key cancer-related genes. This inhibition also affected mucin secretion and mucin variants production. Collectively, our findings provide the first evidence for dysregulation of the genes of pivotal RNA-regulatory processes in PMP, implying that these targetable mechanisms may be functionally altered and play a role in the disease. Hence, a thorough understanding of its RNA biology could aid in the discovery of new clinically actionable vulnerabilities in this rare disease.