1. Cancer Biology

Mutant SF3B1 promotes malignancy in PDAC

  1. Patrik Simmler
  2. Eleonora I Ioannidi
  3. Tamara Mengis
  4. Kim Fabiano Marquart
  5. Simran Asawa
  6. Kjong Van-Lehmann
  7. André Khales
  8. Tinu Thomas
  9. Cornelia Schwerdel
  10. Nicola Aceto
  11. Gunnar Rätsch
  12. Markus Stoffel
  13. Gerald Schwank  Is a corresponding author
  1. ETH Zurich, Switzerland
  2. University of Zurich, Switzerland
  3. University Hospital of Zurich, Switzerland
https://doi.org/10.7554/eLife.80683
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Cite this article
  1. Patrik Simmler
  2. Eleonora I Ioannidi
  3. Tamara Mengis
  4. Kim Fabiano Marquart
  5. Simran Asawa
  6. Kjong Van-Lehmann
  7. André Khales
  8. Tinu Thomas
  9. Cornelia Schwerdel
  10. Nicola Aceto
  11. Gunnar Rätsch
  12. Markus Stoffel
  13. Gerald Schwank
(2023)
Mutant SF3B1 promotes malignancy in PDAC
eLife 12:e80683.
https://doi.org/10.7554/eLife.80683
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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).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Patrik Simmler

    Department of Biology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  2. Eleonora I Ioannidi

    Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  3. Tamara Mengis

    Center of Experimental Rheumatology, University Hospital of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Kim Fabiano Marquart

    Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  5. Simran Asawa

    Department of Biology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  6. Kjong Van-Lehmann

    Department of Computer Science, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  7. André Khales

    Department of Computer Science, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  8. Tinu Thomas

    Department of Computer Science, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  9. Cornelia Schwerdel

    Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  10. Nicola Aceto

    Department of Biology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  11. Gunnar Rätsch

    Department of Computer Science, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  12. Markus Stoffel

    Department of Biology, ETH Zurich, Zurich, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1304-5817

  13. Gerald Schwank

    Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
    For correspondence
    schwank@pharma.uzh.ch
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0767-2953

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.

Reviewing Editor

  1. Erica A Golemis, Fox Chase Cancer Center, United States

Ethics

Animal experimentation: All animal experiments were conducted in accordance with the Swiss Federal Veterinary Office (BVET) guidelines (license no. ZH055/17).

Version history

  1. Received: May 31, 2022
  2. Preprint posted: June 19, 2022 (view preprint)
  3. Accepted: October 11, 2023
  4. Accepted Manuscript published: October 12, 2023 (version 1)
  5. Accepted Manuscript updated: October 16, 2023 (version 2)
  6. Version of Record published: November 7, 2023 (version 3)

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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  1. Patrik Simmler
  2. Eleonora I Ioannidi
  3. Tamara Mengis
  4. Kim Fabiano Marquart
  5. Simran Asawa
  6. Kjong Van-Lehmann
  7. André Khales
  8. Tinu Thomas
  9. Cornelia Schwerdel
  10. Nicola Aceto
  11. Gunnar Rätsch
  12. Markus Stoffel
  13. Gerald Schwank
(2023)
Mutant SF3B1 promotes malignancy in PDAC
eLife 12:e80683.
https://doi.org/10.7554/eLife.80683

Share this article

https://doi.org/10.7554/eLife.80683

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