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Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug.
Alors-Perez, Emilia; Blázquez-Encinas, Ricardo; Alcalá, Sonia; Viyuela-García, Cristina; Pedraza-Arevalo, Sergio; Herrero-Aguayo, Vicente; Jiménez-Vacas, Juan M; Mafficini, Andrea; Sánchez-Frías, Marina E; Cano, María T; Abollo-Jiménez, Fernando; Marín-Sanz, Juan A; Cabezas-Sainz, Pablo; Lawlor, Rita T; Luchini, Claudio; Sánchez, Laura; Sánchez-Hidalgo, Juan M; Ventura, Sebastián; Martin-Hijano, Laura; Gahete, Manuel D; Scarpa, Aldo; Arjona-Sánchez, Álvaro; Ibáñez-Costa, Alejandro; Sainz, Bruno; Luque, Raúl M; Castaño, Justo P.
Afiliación
  • Alors-Perez E; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.
  • Blázquez-Encinas R; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.
  • Alcalá S; Reina Sofia University Hospital, Córdoba, Spain.
  • Viyuela-García C; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain.
  • Pedraza-Arevalo S; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.
  • Herrero-Aguayo V; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.
  • Jiménez-Vacas JM; Reina Sofia University Hospital, Córdoba, Spain.
  • Mafficini A; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain.
  • Sánchez-Frías ME; Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Department of Cancer Biology, Instituto de Investigaciones Biomédicas Alberto Sols (IIBM), CSIC-UAM, Madrid, Spain.
  • Cano MT; Department of Cancer Biology, Chronic Diseases and Cancer Area 3-Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain.
  • Abollo-Jiménez F; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.
  • Marín-Sanz JA; Reina Sofia University Hospital, Córdoba, Spain.
  • Cabezas-Sainz P; Surgery Service, Reina Sofia University Hospital, Córdoba, Spain.
  • Lawlor RT; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.
  • Luchini C; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.
  • Sánchez L; Reina Sofia University Hospital, Córdoba, Spain.
  • Sánchez-Hidalgo JM; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain.
  • Ventura S; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.
  • Martin-Hijano L; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.
  • Gahete MD; Reina Sofia University Hospital, Córdoba, Spain.
  • Scarpa A; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain.
  • Arjona-Sánchez Á; Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Córdoba, Spain.
  • Ibáñez-Costa A; Department of Cell Biology, Physiology, and Immunology, University of Cordoba, Córdoba, Spain.
  • Sainz B; Reina Sofia University Hospital, Córdoba, Spain.
  • Luque RM; CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Avenida Menéndez Pidal s/n, Edificio IMIBIC, 14004, Córdoba, Spain.
  • Castaño JP; ARC-Net Research Centre, University and Hospital Trust of Verona, Verona, Italy.
J Exp Clin Cancer Res ; 40(1): 382, 2021 Dec 02.
Article en En | MEDLINE | ID: mdl-34857016
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Células Madre Neoplásicas / Adenocarcinoma / Carcinoma Ductal Pancreático / Factores de Empalme de ARN Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Exp Clin Cancer Res Año: 2021 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fosfoproteínas / Células Madre Neoplásicas / Adenocarcinoma / Carcinoma Ductal Pancreático / Factores de Empalme de ARN Tipo de estudio: Prognostic_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: J Exp Clin Cancer Res Año: 2021 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido