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Mutant SF3B1 promotes malignancy in PDAC


Abstract

The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1$^{K700E}$ on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1$^{K700E}$ 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 Sf3b1$^{K700E}$ 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 SF3B1$^{K700E}$ 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 SF3B1$^{K700E}$ 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.

Abstract

The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1$^{K700E}$ on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1$^{K700E}$ 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 Sf3b1$^{K700E}$ 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 SF3B1$^{K700E}$ 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 SF3B1$^{K700E}$ 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.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Pharmacology and Toxicology
07 Faculty of Science > Institute of Pharmacology and Toxicology
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Scopus Subject Areas:Life Sciences > General Neuroscience
Life Sciences > General Biochemistry, Genetics and Molecular Biology
Life Sciences > General Immunology and Microbiology
Language:English
Date:12 October 2023
Deposited On:24 Jan 2024 11:34
Last Modified:30 Jun 2024 01:37
Publisher:eLife Sciences Publications Ltd.
ISSN:2050-084X
OA Status:Gold
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.7554/eLife.80683
PubMed ID:37823551
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)