Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Eleonora I Ioannidi
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Tamara Mengis
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Kim Fabiano Marquart
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland; Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Simran Asawa
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
Kjong Van-Lehmann
Department of Computer Science, Biomedical Informatics Group, ETH Zurich, Zurich, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Andre Kahles
Department of Computer Science, Biomedical Informatics Group, ETH Zurich, Zurich, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Tinu Thomas
Department of Computer Science, Biomedical Informatics Group, ETH Zurich, Zurich, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland
Cornelia Schwerdel
Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Nicola Aceto
Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland
Gunnar Rätsch
Department of Computer Science, Biomedical Informatics Group, ETH Zurich, Zurich, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland; Department of Biology, ETH Zurich, Zurich, Switzerland; Biomedical Informatics Research, University Hospital Zurich, Zurich, Switzerland
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.
