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Updated: Sep 17, 2025
Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
UPF1 deficiency enhances mitochondrial ROS which promotes an immunosuppressive microenvironment in pancreatic ductal
Wenjuan Su1, Juan Kochen Rossi1, Cristina Nuevo-Tapioles1
1Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016.
Abstract:
Upstream frameshift 1 (UPF1) is an RNA helicase involved in a number of mRNA regulatory processes including nonsense-mediated decay. Mutations in the UPF1 locus that reduce its expression have been associated with adenosquamous carcinoma of the pancreas, a particularly aggressive form of the disease. To determine the effect of Upf1 suppression in a murine model of pancreatic adenocarcinoma, we silenced with shRNA Upf1 in cells derived from an autochthonous tumor in an LSL-KrasG12D/+; Trp53R172H/+; Pdx-1Cre/+ mouse (KPC) and orthotopically implanted these cells in the pancreas of C57BL/6 mice. Tumors derived from Upf1-deficient cells were markedly larger than those derived from control cells, a difference observed only in immunocompetent mice. The immune infiltrate of Upf1-deficient tumors was enriched in myeloid-derived suppressor cells (MDSCs) and depleted of CD8+ cells compared to control KPC tumors. Upf1-deficient KPC cells secreted inflammatory cytokines including G-CSF and CXCL2, known to recruit MDSCs. Cytokine secretion from Upf1-deficient KPC cells was induced by increased levels of mitochondrial reactive oxygen species (ROS), which in turn were due to an increase in complex I activity in the electron transport chain. Thus, Upf1 helicase deficiency leads to increased mitochondrial complex I activity which produces ROS that signals for cytokine release that drives immune suppression and enhanced tumor growth.
Insights
Upstream frameshift 1 (UPF1) deficiency in pancreatic cancer cells enhances tumor growth by promoting immune suppression. This occurs through increased mitochondrial activity, reactive oxygen species production, and inflammatory cytokine release, leading to myeloid-derived suppressor cell enrichment.
Area of Science:
- Molecular Biology
- Cancer Biology
- Immunology
Background:
- Upstream frameshift 1 (UPF1) is an RNA helicase crucial for mRNA regulation, including nonsense-mediated decay.
- Reduced UPF1 expression is linked to aggressive pancreatic adenosquamous carcinoma.
- Understanding UPF1's role in pancreatic cancer progression is vital for developing new therapies.
Purpose of the Study:
- To investigate the impact of UPF1 suppression on pancreatic adenocarcinoma growth in a murine model.
- To elucidate the mechanisms by which UPF1 deficiency influences the tumor microenvironment and immune response.
Main Methods:
- Silencing UPF1 using shRNA in KPC mouse pancreatic cancer cells.
- Orthotopic implantation of UPF1-silenced and control cells into immunocompetent C57BL/6 mice.
- Analysis of tumor growth, immune cell infiltration (MDSCs, CD8+ T cells), cytokine secretion, mitochondrial activity, and ROS levels.
Main Results:
- UPF1-deficient tumors exhibited significantly larger growth compared to controls, specifically in immunocompetent hosts.
- UPF1 deficiency led to increased myeloid-derived suppressor cells (MDSCs) and decreased CD8+ T cells within tumors.
- UPF1-deficient cells secreted elevated levels of G-CSF and CXCL2, attracting MDSCs, driven by increased mitochondrial complex I activity and ROS production.
Conclusions:
- UPF1 deficiency promotes pancreatic tumor growth by creating an immunosuppressive microenvironment.
- This immune suppression is mediated by increased mitochondrial ROS signaling, leading to cytokine release and MDSC recruitment.
- Targeting UPF1 or its downstream pathways may offer therapeutic strategies for pancreatic cancer.
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