Alors-Pérez, EmiliaBlázquez-Encinas, RicardoAlcala Reyes, SoniaPedraza-Arevalo, SergioHerrero-Aguayo, VicenteJiménez-Vacas, JuanMafficini, AndreaAbollo Jiménez, FernandoMarín Sanz, Juan AntonioCabezas Sáinz, Pablolawlor, RitaLuchini, ClaudioSánchez Piñón, LauraSánchez Hidalgo, Juan AVentura, SebastiánMartin Hijano, LauraGahete, Manuel D.Scarpa, AldoArjona Sánchez, ÁlvaroIbáñez-Costa, AlejandroSainz Anding, BrunoLuque, Raúl M.Castaño, Justo PSánchez Frías, Marina E.Cano, María T.Viyuela, Cristina2024-01-252024-01-252021Alors-Perez, E., Blázquez-Encinas, R., Alcalá, S. et al. Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug. J Exp Clin Cancer Res 40, 382 (2021)1756-9966http://hdl.handle.net/10347/31990Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, requiring novel treatments to target both cancer cells and cancer stem cells (CSCs). Altered splicing is emerging as both a novel cancer hallmark and an attractive therapeutic target. The core splicing factor SF3B1 is heavily altered in cancer and can be inhibited by Pladienolide-B, but its actionability in PDAC is unknown. We explored the presence and role of SF3B1 in PDAC and interrogated its potential as an actionable target. Methods: SF3B1 was analyzed in PDAC tissues, an RNA-seq dataset, and publicly available databases, examining associations with splicing alterations and key features/genes. Functional assays in PDAC cell lines and PDX-derived CSCs served to test Pladienolide-B treatment effects in vitro, and in vivo in zebrafish and mice. Results: SF3B1 was overexpressed in human PDAC and associated with tumor grade and lymph-node involvement. SF3B1 levels closely associated with distinct splicing event profiles and expression of key PDAC players (KRAS, TP53). In PDAC cells, Pladienolide-B increased apoptosis and decreased multiple tumor-related features, including cell proliferation, migration, and colony/sphere formation, altering AKT and JNK signaling, and favoring proapoptotic splicing variants (BCL-XS/BCL-XL, KRASa/KRAS, Δ133TP53/TP53). Importantly, Pladienolide-B similarly impaired CSCs, reducing their stemness capacity and increasing their sensitivity to chemotherapy. Pladienolide-B also reduced PDAC/CSCs xenograft tumor growth in vivo in zebrafish and in miceeng© The Authors 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International Licensehttp://creativecommons.org/licenses/by/4.0/Splicing-spliceosomeSF3B1Pladienolide-BPancreatic cancerCancer stem cellsPancreatic cancerjournal article10.1186/s13046-021-02153-9open access