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-Perez, Emilia
A1 Blázquez-Encinas, Ricardo
A1 Alcalá, Sonia
A1 Viyuela-García, Cristina
A1 Pedraza-Arevalo, Sergio
A1 Herrero-Aguayo, Vicente
A1 Jiménez-Vacas, Juan M.
A1 Mafficini, Andrea
A1 Sánchez-Frías, Marina E.
A1 Cano, María T.
A1 Abollo-Jiménez, Fernando
A1 Marín-Sanz, Juan A.
A1 Cabezas-Sainz, Pablo
A1 Lawlor, Rita T.
A1 Luchini, Claudio
A1 Sánchez, Laura
A1 Sánchez-Hidalgo, Juan M.
A1 Ventura, Sebastián
A1 Martin-Hijano, Laura
A1 Gahete, Manuel D.
A1 Scarpa, Aldo
A1 Arjona-Sánchez, Álvaro
A1 Ibáñez-Costa, Alejandro
A1 Sainz, Bruno
A1 Luque, Raúl M.
A1 Castaño, Justo P.
K1 Pancreatic cancer
K1 Splicing-spliceosome
K1 SF3B1
K1 Pladienolide-B
K1 Cancer stem cells
K1 Carcinoma, pancreatic ductal
K1 Cell proliferation
K1 Apoptosis
K1 Cell line
K1 Neoplasias pancreáticas
K1 Empalmosomas
K1 Células madre neoplásicas
K1 Carcinoma ductal pancreático
K1 Proliferación celular
K1 Línea celular
AB BackgroundPancreatic 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.MethodsSF3B1 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.ResultsSF3B1 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.ConclusionSF3B1 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.
PB BioMed Central, Springer Nature
YR 2021
FD 2021-12-02
LK http://hdl.handle.net/10668/4513
UL http://hdl.handle.net/10668/4513
LA en
NO Alors-Perez E, Blázquez-Encinas R, Alcalá S, Viyuela-García C, Pedraza-Arevalo S, Herrero-Aguayo V, 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. 2021 Dec 2;40(1):382
DS RISalud
RD Apr 9, 2025