ArticleJournal of experimental & clinical cancer research : CR2021
Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug.
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 57 citations in OpenAlex.
- The Role of Splicing Machinery as a Promising Potential Therapeutic Target for Pituitary Neuroendocrine Tumors (PitNETs).Cancers · 2026Review
- Spliceosome induction is a druggable dependency of RAS-driven senescence and cancer.Nature communications · 2026Article
- Review
- Molecular Pathology of Pancreatic Ductal Adenocarcinoma.Cancers · 2025Review
- Systematic characterization of full-length RNA isoforms in human colorectal cancer at single-cell resolution.Protein & cell · 2025Article
- Impaired splicing machinery in craniopharyngiomas unveils PRPF8 and RAVER1 as novel biomarkers and therapeutic targets.Acta neuropathologica communications · 2025Article
- Exploring RNA biology in pseudomyxoma peritonei uncovers splicing dysregulation as a novel, targetable molecular vulnerability.Cancer gene therapy · 2025Article
- Alternative Splicing in Tumorigenesis and Cancer Therapy.Biomolecules · 2025Review
- Targeting RNA splicing modulation: new perspectives for anticancer strategy?Journal of experimental & clinical cancer research : CR · 2025Review
- The splicing machinery is dysregulated and represents a therapeutic vulnerability in breast cancer.Cellular and molecular life sciences : CMLS · 2024Article
- The Exon Junction Complex component EIF4A3 plays a splicing-linked oncogenic role in pancreatic ductal adenocarcinoma.Cancer gene therapy · 2024Article
- Spliceosomic dysregulation in pancreatic cancer uncovers splicing factors PRPF8 and RBMX as novel candidate actionable targets.Molecular oncology · 2024Article
- Drug tolerant persister cell plasticity in cancer: A revolutionary strategy for more effective anticancer therapies.Signal transduction and targeted therapy · 2024Review
- Splicing Machinery Is Impaired in Oral Squamous Cell Carcinomas and Linked to Key Pathophysiological Features.International journal of molecular sciences · 2024Article
- Review
- Altered CELF4 splicing factor enhances pancreatic neuroendocrine tumors aggressiveness influencing mTOR and everolimus response.Molecular therapy. Nucleic acids · 2024Article
- An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer.Cell reports. Medicine · 2024Article
- Broad variation in response of individual introns to splicing inhibitors in a humanized yeast strain.RNA (New York, N.Y.) · 2024Article
- Exploring Splicing Modulation as an Innovative Approach to Combat Pancreatic Cancer: SF3B1 Emerges as a Prognostic Indicator and Therapeutic Target.International journal of biological sciences · 2024Article
- Altered splicing machinery in lung carcinoids unveils NOVA1, PRPF8 and SRSF10 as novel candidates to understand tumor biology and expand biomarker discovery.Journal of translational medicine · 2023Article
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Authors and funding
26 authors at 5 institutions in 3 countries.
Funding
Abstract
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.
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