{"doi":"10.1073/pnas.2401996121","title":"UPF1 deficiency enhances mitochondrial ROS which promotes an immunosuppressive microenvironment in pancreatic ductal adenocarcinoma","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-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.","journal":"Proceedings of the National Academy of Sciences","year":2024,"id":451639,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.959,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":671014,"name":"Juan Andres Kochen Rossi","orcid":"0000-0001-6452-0249","position":1,"is_corresponding":false},{"id":867121,"name":"Cristina Nuevo‐Tapioles","orcid":"0000-0001-5809-2030","position":2,"is_corresponding":false},{"id":227601,"name":"Ting Chen","orcid":"0000-0003-1725-7956","position":3,"is_corresponding":false},{"id":2214,"name":"Emily Kawaler","orcid":"0000-0002-7438-7282","position":4,"is_corresponding":false},{"id":1263008,"name":"Cristina Branco","orcid":"0000-0001-6953-4922","position":5,"is_corresponding":false},{"id":20939,"name":"Kwok‐Kin Wong","orcid":"0000-0001-6323-235X","position":6,"is_corresponding":false},{"id":106458,"name":"Diane M. Simeone","orcid":"0000-0001-5142-3087","position":7,"is_corresponding":false},{"id":1273044,"name":"Lawrence B. Gardner","orcid":"0000-0003-0191-0172","position":8,"is_corresponding":false},{"id":251203,"name":"Mark R. Philips","orcid":"0000-0002-1179-8156","position":9,"is_corresponding":false},{"id":1263007,"name":"Wenjuan Su","orcid":"0000-0002-2398-5100","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:02:45.951080Z","pmid":"40591563","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}