Affiliation:
1. IMIBIC: Instituto Maimonides de Investigacion Biomedica de Cordoba
2. Universidad Autónoma de Madrid Facultad de Medicina: Universidad Autonoma de Madrid Facultad de Medicina
3. Reina Sofía Hospital: Hospital Reina Sofia
4. University of Verona: Universita degli Studi di Verona
5. Universidad de Santiago de Compostela: Universidade de Santiago de Compostela
6. Universidad Autónoma de Madrid: Universidad Autonoma de Madrid
Abstract
Abstract
Background
Pancreatic ductal adenocarcinoma (PDAC) remains an appallingly lethal cancer, requiring novel treatments to target both cancer cells and cancer stem cells (CSCs). Altered splicing is emerging as a novel cancer hallmark and 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 poorly known. We explore the presence and role of SF3B1 in PDAC and interrogate its potential as an actionable target.
Methods
SF3B1 was analyzed in PDAC tissues, a RNA-seq dataset, and public 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/or mice.
Conclusion
SF3B1 overexpression is 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.
Publisher
Research Square Platform LLC
Cited by
1 articles.
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