Mutant SF3B1 promotes malignancy in PDAC
- ETH Zurich, Switzerland
- University of Zurich, Switzerland
- University Hospital of Zurich, Switzerland
Abstract
The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1K700E on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1K700E alone is insufficient to induce malignant transformation of the murine pancreas, but that it increases aggressiveness of PDAC if it co-occurs with mutated KRAS and p53. We further show that Sf3b1K700E already plays a role during early stages of pancreatic tumor progression and reduces the expression of TGF-β1-responsive epithelial-mesenchymal transition (EMT) genes. Moreover, we found that SF3B1K700E confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of Map3k7. Overall, our findings demonstrate that SF3B1K700E acts as an oncogenic driver in PDAC, and suggest that it promotes the progression of early stage tumors by impeding the cellular response to tumor suppressive effects of TGF-β.
Data availability
The RNA sequencing raw data of sorted murine cancer cells was deposited in the NCBI Gene Expression Omnibus (GEO) under accession number GSE203339. Splice analysis of human cancers was performed on a previously published dataset, accessible at https://gdc.cancer.gov/about-data/publications/PanCanAtlas-Splicing-2018 (Kahles et al., 2018).
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RNA-seq of sorted KPC Sf3b1-K700E murine PDAC cellsNCBI Gene Expression Omnibus, GSE203339.
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Author details
Funding
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (185293)
- Patrik Simmler
- Eleonora I Ioannidi
- Tamara Mengis
- Kim Fabiano Marquart
- Cornelia Schwerdel
- Gerald Schwank
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (176317)
- Patrik Simmler
European Research Council (101001652)
- Simran Asawa
- Nicola Aceto
Personalized Health and Related Technologies at ETH Zurich (PHRT-541)
- Simran Asawa
- Nicola Aceto
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (212183)
- Simran Asawa
- Nicola Aceto
Swiss Cancer League (KLS-4834-08-2019)
- Simran Asawa
- Nicola Aceto
ETH Lymphoma Challenge (LC-02-22)
- Simran Asawa
- Nicola Aceto
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were conducted in accordance with the Swiss Federal Veterinary Office (BVET) guidelines (license no. ZH055/17).
Copyright
© 2023, Simmler et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mutant SF3B1 promotes malignancy in PDAC
eLife 12:e80683.
https://doi.org/10.7554/eLife.80683
