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Mutant SF3B1 promotes malignancy in PDAC
Patrik Simmler1,2, Eleonora I Ioannidi2, Tamara Mengis2
1Department of Biology, Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland.
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.
Insights
The SF3B1K700E mutation drives pancreatic cancer aggressiveness, particularly with KRAS and p53 mutations. This splicing factor impedes TGF-β1
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- The splicing factor SF3B1 is frequently mutated in pancreatic ductal adenocarcinoma (PDAC).
- The specific role of the SF3B1K700E hotspot mutation in PDAC pathogenesis is not well understood.
Purpose of the Study:
- To investigate the impact of the SF3B1K700E mutation on pancreatic cancer development and progression.
- To elucidate the molecular mechanisms by which SF3B1K700E influences PDAC aggressiveness and response to TGF-β1 signaling.
Main Methods:
- Utilized murine models to assess the oncogenic potential of Sf3b1K700E alone and in combination with KRAS and p53 mutations.
- Analyzed the expression of TGF-β1-responsive genes and epithelial-mesenchymal transition (EMT) markers in pancreatic tumors.
- Investigated the effect of SF3B1K700E on TGF-β1-induced cell death in pancreatic organoids and cell lines.
- Examined the aberrant splicing of downstream targets, such as Map3k7, in SF3B1K700E-mutated cells.
Main Results:
- Sf3b1K700E alone does not induce pancreatic malignancy but enhances PDAC aggressiveness when co-occurring with KRAS and p53 mutations.
- Sf3b1K700E impacts early pancreatic tumor progression by reducing the expression of TGF-β1-responsive EMT genes.
- SF3B1K700E confers resistance to TGF-β1-induced cell death in pancreatic cells and organoids.
- Aberrant splicing of Map3k7 is implicated in the SF3B1K700E-mediated resistance to TGF-β1.
Conclusions:
- SF3B1K700E functions as an oncogenic driver in PDAC.
- This mutation promotes early-stage tumor progression by interfering with the cellular response to tumor-suppressive TGF-β1 signaling.
