An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer

#Gastrin I ; #1003377 ;

Cell Reports Medicine, 2024, 101411, ISSN 2666-3791.

Veronica Ruta ¹, Chiara Naro ², Marco Pieraccioli ², Adriana Leccese ¹, Livia Archibugi ³, Eleonora Cesari ⁴, Valentina Panzeri ¹, Chantal Allgöwer ⁵, Paolo Giorgio Arcidiacono ⁶, Massimo Falconi ⁷, Carmine Carbone ⁴, Giampaolo Tortora ⁸, Federica Borrelli ⁴, Fabia Attili ⁴, Cristiano Spada ⁴, Giuseppe Quero ⁹, Sergio Alfieri ⁹, Claudio Doglioni ¹⁰, Alexander Kleger ¹¹, Gabriele Capurso ⁶, Claudio Sette ¹²

Affiliations expand

• PMID: 38325381
• PMCID: PMC10897606
• DOI: 10.1016/j.xcrm.2024.101411

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. PDAC presents with molecularly distinct subtypes, with the basal-like one being associated with enhanced chemoresistance. Splicing dysregulation contributes to PDAC; however, its involvement in subtype specification remains elusive. Herein, we uncover a subtype-specific splicing signature associated with prognosis in PDAC and the splicing factor Quaking (QKI) as a determinant of the basal-like signature. Single-cell sequencing analyses highlight QKI as a marker of the basal-like phenotype. QKI represses splicing events associated with the classical subtype while promoting basal-like events associated with shorter survival. QKI favors a plastic, quasi-mesenchymal phenotype that supports migration and chemoresistance in PDAC organoids and cell lines, and its expression is elevated in high-grade primary tumors and metastatic lesions. These studies identify a splicing signature that defines PDAC subtypes and indicate that QKI promotes an undifferentiated, plastic phenotype, which renders PDAC cells chemoresistant and adaptable to environmental changes.