Mutant SF3B1 promotes malignancy in PDAC.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 37823551.
- Also identified by DOI 10.7554/eLife.80683 and PMC identifier 10629822.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
The splicing factor SF3B1 is recurrently mutated in various tumors, including pancreatic ductal adenocarcinoma (PDAC). The impact of the hotspot mutation SF3B1<sup>K700E</sup> on the PDAC pathogenesis, however, remains elusive. Here, we demonstrate that Sf3b1<sup>K700E</sup> 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<sup>K700E</sup> 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<sup>K700E</sup> confers resistance to TGF-β1-induced cell death in pancreatic organoids and cell lines, partly mediated through aberrant splicing of <i>Map3k7</i>. Overall, our findings demonstrate that SF3B1<sup>K700E</sup> 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.
Medical subject headings
- Carcinoma, Pancreatic Ductal
- Pancreatic Neoplasms