RT Journal Article
T1 Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
A1 Alors-Pérez, Emilia
A1 Blázquez-Encinas, Ricardo
A1 Alcala Reyes, Sonia
A1 Pedraza-Arevalo, Sergio
A1 Herrero-Aguayo, Vicente
A1 Jiménez-Vacas, Juan
A1 Mafficini, Andrea
A1 Abollo Jiménez, Fernando
A1 Marín Sanz, Juan Antonio
A1 Cabezas Sáinz, Pablo
A1 lawlor, Rita
A1 Luchini, Claudio
A1 Sánchez Piñón, Laura
A1 Sánchez Hidalgo, Juan A
A1 Ventura, Sebastián
A1 Martin Hijano, Laura
A1 Gahete, Manuel D.
A1 Scarpa, Aldo
A1 Arjona Sánchez, Álvaro
A1 Ibáñez-Costa, Alejandro
A1 Sainz Anding, Bruno
A1 Luque, Raúl M.
A1 Castaño, Justo P
A1 Sánchez Frías, Marina E.
A1 Cano, María T.
A1 Viyuela, Cristina
K1 Splicing-spliceosome
K1 SF3B1
K1 Pladienolide-B
K1 Pancreatic cancer
K1 Cancer stem cells
AB Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, requiring novel treatments totarget both cancer cells and cancer stem cells (CSCs). Altered splicing is emerging as both a novel cancer hallmarkand an attractive therapeutic target. The core splicing factor SF3B1 is heavily altered in cancer and can be inhibitedby Pladienolide-B, but its actionability in PDAC is unknown. We explored the presence and role of SF3B1 in PDAC andinterrogated its potential as an actionable target.Methods: SF3B1 was analyzed in PDAC tissues, an RNA-seq dataset, and publicly available databases, examiningassociations with splicing alterations and key features/genes. Functional assays in PDAC cell lines and PDX-derivedCSCs 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). InPDAC 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 splicingvariants (BCL-XS/BCL-XL, KRASa/KRAS, Δ133TP53/TP53). Importantly, Pladienolide-B similarly impaired CSCs, reducingtheir stemness capacity and increasing their sensitivity to chemotherapy. Pladienolide-B also reduced PDAC/CSCsxenograft tumor growth in vivo in zebrafish and in mice
PB Springer
SN 1756-9966
YR 2021
FD 2021
LK http://hdl.handle.net/10347/31990
UL http://hdl.handle.net/10347/31990
LA eng
NO Alors-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)
NO 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 (BIO-0139). 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)Authors gratefully acknowledge Dr. FX Real who generously provided the HPDE E6E7 cell line, and all patients for generously donating the samples studies in this work
DS Minerva
RD 23 abr 2026