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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Pancreatic Cancer | Research

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

Authors: 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 Jr, Raúl M. Luque, Justo P. Castaño

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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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.
Appendix
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Metadata
Title
Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug
Authors
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 Jr
Raúl M. Luque
Justo P. Castaño
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02153-9

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