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.
Article and author information
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
Further reading
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The immunosuppressive microenvironment in pancreatic ductal adenocarcinoma (PDAC) prevents tumor control and strategies to restore anti-cancer immunity (i.e. by increasing CD8 T-cell activity) have had limited success. Here, we demonstrate how inducing localized physical damage using ionizing radiation (IR) unmasks the benefit of immunotherapy by increasing tissue-resident natural killer (trNK) cells that support CD8 T activity. Our data confirms that targeting mouse orthotopic PDAC tumors with IR together with CCR5 inhibition and PD1 blockade reduces E-cadherin positive tumor cells by recruiting a hypoactive NKG2D-ve NK population, phenotypically reminiscent of trNK cells, that supports CD8 T-cell involvement. We show an equivalent population in human single-cell RNA sequencing (scRNA-seq) PDAC cohorts that represents immunomodulatory trNK cells that could similarly support CD8 T-cell levels in a cDC1-dependent manner. Importantly, a trNK signature associates with survival in PDAC and other solid malignancies revealing a potential beneficial role for trNK in improving adaptive anti-tumor responses and supporting CCR5 inhibitor (CCR5i)/αPD1 and IR-induced damage as a novel therapeutic approach.
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