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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,13]]},"abstract":"<jats:p>\n                    Upstream frameshift 1 (UPF1) is an RNA helicase involved in a number of mRNA regulatory processes including nonsense-mediated decay. Mutations in the\n                    <jats:italic>UPF1<\/jats:italic>\n                    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\n                    <jats:italic>Upf1<\/jats:italic>\n                    suppression in a murine model of pancreatic adenocarcinoma, we silenced with shRNA\n                    <jats:italic>Upf1<\/jats:italic>\n                    in cells derived from an autochthonous tumor in an LSL-Kras\n                    <jats:sup>G12D\/+<\/jats:sup>\n                    ; Trp53\n                    <jats:sup>R172H\/+<\/jats:sup>\n                    ; Pdx-1\n                    <jats:sup>Cre\/+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2401996121","type":"journal-article","created":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T13:45:07Z","timestamp":1722951907000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":6,"title":["UPF1 deficiency enhances mitochondrial ROS which promotes an immunosuppressive microenvironment in pancreatic ductal adenocarcinoma"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2398-5100","authenticated-orcid":false,"given":"Wenjuan","family":"Su","sequence":"first","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6452-0249","authenticated-orcid":false,"given":"Juan","family":"Kochen Rossi","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5809-2030","authenticated-orcid":false,"given":"Cristina","family":"Nuevo-Tapioles","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Kawaler","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Branco","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwok-kin","family":"Wong","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane M.","family":"Simeone","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California, San Diego, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence B.","family":"Gardner","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1179-8156","authenticated-orcid":false,"given":"Mark R.","family":"Philips","sequence":"additional","affiliation":[{"name":"Perlmutter Cancer Center, New York University Grossman School of Medicine, New York, NY 10016"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,6]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.02.014"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3390\/curroncol29100541"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0363-5"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature16965"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2018.02.003"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.10.051"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3548"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.62209"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.070136.118"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1002\/wrna.1168"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.01.021"},{"key":"e_1_3_4_12_2","first-page":"8956","article-title":"LncRNA PVT1 aggravates the progression of glioma via downregulating UPF1","volume":"23","author":"Lv Z. 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