{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:32:54Z","timestamp":1793298774167,"version":"4.5.0"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"50","license":[{"start":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T00:00:00Z","timestamp":1733184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004410","name":"European Molecular Biology Organization","doi-asserted-by":"publisher","award":["ALTF 578-2017"],"award-info":[{"award-number":["ALTF 578-2017"]}],"id":[{"id":"10.13039\/100004410","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C219\/A23522"],"award-info":[{"award-number":["C219\/A23522"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["096540\/Z\/11\/Z"],"award-info":[{"award-number":["096540\/Z\/11\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100022431","name":"UKRI | MRC | Medical Research Council Centre for Neurodevelopmental Disorders","doi-asserted-by":"publisher","award":["G1100073"],"award-info":[{"award-number":["G1100073"]}],"id":[{"id":"10.13039\/501100022431","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,12,10]]},"abstract":"<jats:p>\n                    Oral squamous cell carcinoma (OSCC) is a subtype of head and neck cancer that arises in the multilayered epithelia of the mouth and lips. Although inactivating mutations in\n                    <jats:italic toggle=\"yes\">CASP8<\/jats:italic>\n                    are frequently found in human OSCC their role in the disease is unknown. To investigate this, we deleted\n                    <jats:italic toggle=\"yes\">Casp8<\/jats:italic>\n                    in the oral epithelium of adult mice. Loss of Caspase-8 resulted in defects in the tongue epithelial barrier and triggered a neutrophil-rich immune infiltrate distinct from that observed on epidermal\n                    <jats:italic toggle=\"yes\">Casp8<\/jats:italic>\n                    deletion. Oral\n                    <jats:italic toggle=\"yes\">Casp8<\/jats:italic>\n                    deletion led to activation of autophagy. Inhibition of autophagy partially rescued epithelial integrity in\n                    <jats:italic toggle=\"yes\">Casp8<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, while induction of autophagy in wild type mice resulted in oral barrier defects and excessive neutrophil infiltration. On treatment with the carcinogen 4-nitroquinoline-1-oxide\n                    <jats:italic toggle=\"yes\">Casp8<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice showed increased susceptibility to developing oral tumors. Depletion of neutrophils reduced tumor incidence, which correlated with a reduction in reactive oxygen species and decreased epithelial DNA damage. Our findings establish a functional link between epithelial integrity, autophagy, and the tumor immune microenvironment, placing Caspase-8 at the center of these processes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2406944121","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T13:40:03Z","timestamp":1733233203000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Caspase-8-dependent autophagy regulates neutrophil infiltration in oral squamous cell carcinoma"],"prefix":"10.1073","volume":"121","author":[{"given":"Miguel","family":"Bernab\u00e9-Rubio","sequence":"first","affiliation":[{"name":"Centre for Gene Therapy and Regenerative Medicine, School of Basic and Medical Biosciences, King\u2019s College London","place":["London, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9151-5154","authenticated-orcid":false,"given":"Fiona M.","family":"Watt","sequence":"additional","affiliation":[{"name":"Centre for Gene Therapy and Regenerative Medicine, School of Basic and Medical Biosciences, King\u2019s College London","place":["London, United Kingdom"]},{"name":"Directors\u2019 Unit, European Molecular Biology Laboratory Heidelberg","place":["Heidelberg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,12,3]]},"reference":[{"key":"e_1_3_5_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2982"},{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2016.09.014"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14129"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-12-0537"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81266-0"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers2041952"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2020.188357"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.01.020"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2014.10.004"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1096645"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808597105"},{"key":"e_1_3_5_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.08.005"},{"key":"e_1_3_5_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.05.013"},{"key":"e_1_3_5_15_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20081811"},{"key":"e_1_3_5_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00571-6"},{"key":"e_1_3_5_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-019-0222-4"},{"key":"e_1_3_5_18_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20090616"},{"key":"e_1_3_5_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07687"},{"key":"e_1_3_5_20_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009751108"},{"key":"e_1_3_5_21_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2014-307226"},{"key":"e_1_3_5_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1770-6"},{"key":"e_1_3_5_23_2","doi-asserted-by":"publisher","DOI":"10.1002\/hep.21495"},{"key":"e_1_3_5_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10400"},{"key":"e_1_3_5_25_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104138200"},{"key":"e_1_3_5_26_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.132.3.437"},{"key":"e_1_3_5_27_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004706"},{"key":"e_1_3_5_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05872-4"},{"key":"e_1_3_5_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2016.100"},{"key":"e_1_3_5_30_2","doi-asserted-by":"publisher","DOI":"10.1080\/15548627.2015.1100356"},{"key":"e_1_3_5_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.07.012"},{"key":"e_1_3_5_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2004.07.005"},{"key":"e_1_3_5_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2016.52"},{"key":"e_1_3_5_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-998-3_40"},{"key":"e_1_3_5_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2020.101277"},{"key":"e_1_3_5_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01322"},{"key":"e_1_3_5_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-3676"},{"key":"e_1_3_5_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M300513200"},{"key":"e_1_3_5_39_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0022-202X.2004.23225.x"},{"key":"e_1_3_5_40_2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.01888"},{"key":"e_1_3_5_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2014.01.004"},{"key":"e_1_3_5_42_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI122085"},{"key":"e_1_3_5_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.05.010"},{"key":"e_1_3_5_44_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aam9690"},{"key":"e_1_3_5_45_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf6493"},{"key":"e_1_3_5_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1274519"},{"key":"e_1_3_5_47_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.6145"},{"key":"e_1_3_5_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01063"},{"key":"e_1_3_5_49_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.309104"},{"key":"e_1_3_5_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0032-3"},{"key":"e_1_3_5_51_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41556-023-01234-5"}],"updated-by":[{"DOI":"10.1073\/pnas.2635279123","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:00:00Z","timestamp":1793232000000}}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2406944121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:37:38Z","timestamp":1793295458000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2406944121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,3]]},"references-count":51,"journal-issue":{"issue":"50","published-print":{"date-parts":[[2024,12,10]]}},"alternative-id":["10.1073\/pnas.2406944121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2406944121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,3]]},"assertion":[{"value":"2024-04-06","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-12-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2406944121"}}