A New Molecular (P)Layer in Pseudomyxoma Peritonei: The Splicing Machinery is Dysregulated and Linked to Low Survival

Purpose: Pseudomyxoma peritonei (PMP) is a rare cancer that causes chronic and uncontrollable mucus accumulation, gradually leading to intraperitoneal organ adhesion, bowel obstruction, malnutrition, and eventually cachexia and death. Aggressive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy offer the best results; but the probability of relapse remains high. The study of the distinct molecular layers underlying PMP is essential to understand its genesis and progression. Alternative splicing is emerging as a new player in all cancers, but its role in PMP is unknown. The aim of this work was to assess the splicing machinery status in PMP and determine its potential contribution to disease prognosis. Methods: A set of 62 splicing-related genes were evaluated in a cohort of 29 patients using a microfluidic array, and their levels were compared between tumor and non-tumor tissue and correlated to relevant clinical parameters. Selected components were validated by immunohistochemistry and subsequently studied in detail by enrichment analyses. Results: Results revealed a profound dysregulation of the splicing machinery at RNA/protein level, which allowed to distinguish between tumor and control tissues. Particularly, the splicing factors HNRNPK , MBNL1 , PTBP1 and RAVER1 were associated with poor prognosis and their expression was linked to TP53 regulation and inflammation processes. Conclusions: These findings provide the first evidence for the dysregulation of the splicing machinery in PMP, suggesting that it could be functionally altered and play a role in this rare malignant disease. Therefore, its detailed understanding could help to identify novel prognostic biomarkers and therapeutic targets in PMP.