Mutant SF3B1 promotes PDAC malignancy through TGF-β resistance

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 increases aggressiveness of PDAC if it co-occurs together with mutated KRAS and p53. We further demonstrate that SF3B1K700E reduces epithelial–mesenchymal transition (EMT) and confers resistance to TGF-β1-induced cell death, and provide evidence that this phenotype is in part mediated through aberrant splicing of Map3k7. Taken together, our work suggests that SF3B1K700E acts as an oncogenic driver in PDAC through enhancing resistance to the tumor suppressive effects of TGF-β.

Alternative splicing and related RNA binding proteins in human health and disease

“…Most of these studies focus on protein-coding splicing factors, among which SF3B1 is the most extensively studied component. 446 A recent study found that various pathogenic mutations in the SF3B1 gene can alter AS by disrupting the interaction with SUGP1. In the mutant spliceosome, the level of SUGP1 is reduced.…”