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

Abstract 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 SF3B...

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Autores principales:	Emilia Alors-Perez, Ricardo Blázquez-Encinas, Sonia Alcalá, Cristina Viyuela-García, Sergio Pedraza-Arevalo, Vicente Herrero-Aguayo, Juan M. Jiménez-Vacas, Andrea Mafficini, Marina E. Sánchez-Frías, María T. Cano, Fernando Abollo-Jiménez, Juan A. Marín-Sanz, Pablo Cabezas-Sainz, Rita T. Lawlor, Claudio Luchini, Laura Sánchez, Juan M. Sánchez-Hidalgo, Sebastián Ventura, Laura Martin-Hijano, Manuel D. Gahete, Aldo Scarpa, Álvaro Arjona-Sánchez, Alejandro Ibáñez-Costa, Bruno Sainz, Raúl M. Luque, Justo P. Castaño
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Pancreatic cancer Splicing-spliceosome SF3B1 Pladienolide-B cancer stem cells Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/2e57a0d7fd7f42d6a9f88e1c0cae6aca
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spelling	oai:doaj.org-article:2e57a0d7fd7f42d6a9f88e1c0cae6aca2021-12-05T12:10:11ZDysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug10.1186/s13046-021-02153-91756-9966https://doaj.org/article/2e57a0d7fd7f42d6a9f88e1c0cae6aca2021-12-01T00:00:00Zhttps://doi.org/10.1186/s13046-021-02153-9https://doaj.org/toc/1756-9966Abstract 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.Emilia Alors-PerezRicardo Blázquez-EncinasSonia AlcaláCristina Viyuela-GarcíaSergio Pedraza-ArevaloVicente Herrero-AguayoJuan M. Jiménez-VacasAndrea MafficiniMarina E. Sánchez-FríasMaría T. CanoFernando Abollo-JiménezJuan A. Marín-SanzPablo Cabezas-SainzRita T. LawlorClaudio LuchiniLaura SánchezJuan M. Sánchez-HidalgoSebastián VenturaLaura Martin-HijanoManuel D. GaheteAldo ScarpaÁlvaro Arjona-SánchezAlejandro Ibáñez-CostaBruno SainzRaúl M. LuqueJusto P. CastañoBMCarticlePancreatic cancerSplicing-spliceosomeSF3B1Pladienolide-Bcancer stem cellsNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Experimental & Clinical Cancer Research, Vol 40, Iss 1, Pp 1-21 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Pancreatic cancer Splicing-spliceosome SF3B1 Pladienolide-B cancer stem cells Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Pancreatic cancer Splicing-spliceosome SF3B1 Pladienolide-B cancer stem cells Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Emilia Alors-Perez Ricardo Blázquez-Encinas Sonia Alcalá Cristina Viyuela-García Sergio Pedraza-Arevalo Vicente Herrero-Aguayo Juan M. Jiménez-Vacas Andrea Mafficini Marina E. Sánchez-Frías María T. Cano Fernando Abollo-Jiménez Juan A. Marín-Sanz Pablo Cabezas-Sainz Rita T. Lawlor Claudio Luchini Laura Sánchez Juan M. Sánchez-Hidalgo Sebastián Ventura Laura Martin-Hijano Manuel D. Gahete Aldo Scarpa Álvaro Arjona-Sánchez Alejandro Ibáñez-Costa Bruno Sainz Raúl M. Luque Justo P. Castaño Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
description	Abstract 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.
format	article
author	Emilia Alors-Perez Ricardo Blázquez-Encinas Sonia Alcalá Cristina Viyuela-García Sergio Pedraza-Arevalo Vicente Herrero-Aguayo Juan M. Jiménez-Vacas Andrea Mafficini Marina E. Sánchez-Frías María T. Cano Fernando Abollo-Jiménez Juan A. Marín-Sanz Pablo Cabezas-Sainz Rita T. Lawlor Claudio Luchini Laura Sánchez Juan M. Sánchez-Hidalgo Sebastián Ventura Laura Martin-Hijano Manuel D. Gahete Aldo Scarpa Álvaro Arjona-Sánchez Alejandro Ibáñez-Costa Bruno Sainz Raúl M. Luque Justo P. Castaño
author_facet	Emilia Alors-Perez Ricardo Blázquez-Encinas Sonia Alcalá Cristina Viyuela-García Sergio Pedraza-Arevalo Vicente Herrero-Aguayo Juan M. Jiménez-Vacas Andrea Mafficini Marina E. Sánchez-Frías María T. Cano Fernando Abollo-Jiménez Juan A. Marín-Sanz Pablo Cabezas-Sainz Rita T. Lawlor Claudio Luchini Laura Sánchez Juan M. Sánchez-Hidalgo Sebastián Ventura Laura Martin-Hijano Manuel D. Gahete Aldo Scarpa Álvaro Arjona-Sánchez Alejandro Ibáñez-Costa Bruno Sainz Raúl M. Luque Justo P. Castaño
author_sort	Emilia Alors-Perez
title	Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
title_short	Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
title_full	Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
title_fullStr	Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
title_full_unstemmed	Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
title_sort	dysregulated splicing factor sf3b1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
publisher	BMC
publishDate	2021
url	https://doaj.org/article/2e57a0d7fd7f42d6a9f88e1c0cae6aca
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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

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