UPF1 deficiency enhances mitochondrial ROS which promotes an immunosuppressive microenvironment in pancreatic ductal adenocarcinoma

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 121; no. 33; p. 1
Main Authors Su, Wenjuan, Kochen Rossi, Juan, Nuevo-Tapioles, Cristina, Chen, Ting, Kawaler, Emily, Branco, Cristina, Wong, Kwok-kin, Simeone, Diane M., Gardner, Lawrence B., Philips, Mark R.
Format Journal Article
LanguageEnglish
Published Washington National Academy of Sciences 13.08.2024
Subjects
Adenocarcinoma
Adenosquamous
Animal models
Cancer
CD8 antigen
Cytokines
DNA helicase
Electron transport
Electron transport chain
Gene expression
Granulocyte colony-stimulating factor
Microenvironments
Mitochondria
mRNA
mRNA turnover
NADH-ubiquinone oxidoreductase
Oxygen enrichment
Pancreas
Pancreatic carcinoma
Reactive oxygen species
RNA helicase
Squamous cell carcinoma
Suppressor cells
Tumors
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Summary: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-Kras G12D/+ ; Trp53 R172H/+ ; Pdx-1 Cre/+ 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2401996121