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

• 成果类型: Article
• 署名作者: Su, Wenjuan; Rossi, Juan Kochen; Nuevo-Tapioles, Cristina; Chen, Ting; Kawaler, Emily; Branco, Cristina; Wong, Kwok-kin; Simeone, Diane M.; Gardner, Lawrence B.; Philips, Mark R.
• 署名单位: University of California System; University of California San Diego
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11597
• DOI: 10.1073/pnas.2401996121
• 发表日期: 2024-08-13
• 关键词: mediated rna decay; cancer; progression; inhibition; gene

摘要

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.