Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug.

Autor:	Alors-Perez E; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain., Blázquez-Encinas R; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain., Alcalá S; Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain.; Department of Cancer Biology, Chronic Diseases and Cancer Area 3-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Viyuela-García C; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; Surgery Service, Reina Sofia University Hospital, Córdoba, Spain., Pedraza-Arevalo S; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain., Herrero-Aguayo V; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain., Jiménez-Vacas JM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain., Mafficini A; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy., Sánchez-Frías ME; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; Pathology Service, Reina Sofia University Hospital, Córdoba, Spain., Cano MT; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; Medical Oncology Service, Reina Sofia University Hospital, Córdoba, Spain., Abollo-Jiménez F; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Computer Sciences, University of Cordoba, Córdoba, Spain., Marín-Sanz JA; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Computer Sciences, University of Cordoba, Córdoba, Spain., Cabezas-Sainz P; Department of Zoology, Genetics and Physical Anthropology, University of Santiago de Compostela, Lugo, Spain., Lawlor RT; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy., Luchini C; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy.; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Sánchez L; Department of Zoology, Genetics and Physical Anthropology, University of Santiago de Compostela, Lugo, Spain., Sánchez-Hidalgo JM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; Surgery Service, Reina Sofia University Hospital, Córdoba, Spain., Ventura S; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Computer Sciences, University of Cordoba, Córdoba, Spain., Martin-Hijano L; Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain.; Department of Cancer Biology, Chronic Diseases and Cancer Area 3-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain., Gahete MD; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain., Scarpa A; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy.; Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy., Arjona-Sánchez Á; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; Surgery Service, Reina Sofia University Hospital, Córdoba, Spain., Ibáñez-Costa A; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.; Reina Sofia University Hospital, Córdoba, Spain.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain., Sainz B Jr; Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain. bsainz@iib.uam.es.; Centro de Investigación Biomédica en Red, Área Cáncer, CIBERONC, ISCIII, Madrid, Spain. bsainz@iib.uam.es., Luque RM; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain. raul.luque@uco.es.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain. raul.luque@uco.es.; Reina Sofia University Hospital, Córdoba, Spain. raul.luque@uco.es.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain. raul.luque@uco.es., Castaño JP; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain. justo@uco.es.; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain. justo@uco.es.; Reina Sofia University Hospital, Córdoba, Spain. justo@uco.es.; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain. justo@uco.es.
Jazyk:	angličtina
Zdroj:	Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2021 Dec 02; Vol. 40 (1), pp. 382. Date of Electronic Publication: 2021 Dec 02.
DOI:	10.1186/s13046-021-02153-9
Abstrakt:	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. (© 2021. The Author(s).)
Databáze:	MEDLINE
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