Open Access #2 2021
Alors-Perez, Emilia ;
Blázquez-Encinas, Ricardo ;
Alcalá, Sonia ;
Viyuela-García, Cristina ;
Pedraza-Arévalo, Sergio ;
Herrero-Aguayo, Vicente ;
Jiménez-Vacas, Juan M ;
Mafficini, Andrea ;
Sánchez-Frías, Marina E ;
Cano, María T ;
Abollo-Jiménez, Fernando ;
Marín-Sanz, Juan A ;
Cabezas-Sainz, Pablo ;
Lawlor, Rita T ;
Luchini, Claudio ;
Sánchez, Laura ;
Sánchez-Hidalgo, Juan M ;
Ventura, Sebastián ;
Martin-Hijano, Laura ;
Gahete, Manuel D ;
Scarpa, Aldo ;
Arjona-Sánchez, Álvaro ;
Ibáñez-Costa, Alejandro ;
Sainz, Bruno Jr ;
Luque, Raúl M ;
Castaño, Justo P Abstract © The Author(s) 2021. ; [Background]: 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 mice. [Conclusion]. SF3B1 overexpression represents a therapeutic vulnerability in PDAC, as altered splicing can be targeted with Pladienolide-B both in cancer cells and CSCs, paving the way for novel therapies for this lethal cancer. ; This work has been supported by Spanish Ministry of Economy [MINECO; BFU2016–80360-R (to JPC)] and Ministry of Science and Innovation [MICINN; PID2019-105201RB-I00 (to JPC), PID2019-105564RB-I00 (to RML)]. Instituto de Salud Carlos III, co-funded by European Union (ERDF/ESF, "Investing in your future") [FIS Grants PI17/02287 and PI20/01301 (to MDG), PI18/00757 (to BS,Jr); DTS Grant DTS20/00050 (to RML)); Postdoctoral Grant Sara Borrell CD19/00255 (to AIC); Predoctoral contract FI17/00282 (to EAP)]. Coordinated grant (GC16173694BARB) from the Fundación Asociación Española Contra el Cáncer (AECC) (to BS,Jr). Spanish Ministry of Universities [Predoctoral contracts FPU14/04290 (to SPA); FPU16/06190 (to VHA); FPU18/02275 (to RBE)]. Boehringer Ingelheim Fonds travel grant (EAP). Junta de Andalucía (BIO0139). GETNE2016 and GETNE2019 Research grants (to JPC); and CIBERobn. Associazione Italiana Ricerca Cancro (AIRC 5×1000 n. 12182); Fondazione Italiana Malattie Pancreas – Ministero Salute [FIMPCUP_J38D19000690001]; Fondazione Cariverona: Oncology Biobank Project "Antonio Schiavi" (prot.203885/2017).