{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:33:34Z","timestamp":1772156014451,"version":"3.50.1"},"reference-count":32,"publisher":"The Royal Society","issue":"183","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/royalsociety.org\/journals\/ethics-policies\/data-sharing-mining\/"}],"funder":[{"name":"Clare College"},{"name":"Wellcome Sanger Institute","award":["098051"],"award-info":[{"award-number":["098051"]}]},{"name":"Wellcome Sanger Institute","award":["206194"],"award-info":[{"award-number":["206194"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["C609\/A17257"],"award-info":[{"award-number":["C609\/A17257"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"crossref","award":["C609\/A27326"],"award-info":[{"award-number":["C609\/A27326"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000288","name":"Royal Society","doi-asserted-by":"crossref","award":["UF130039"],"award-info":[{"award-number":["UF130039"]}],"id":[{"id":"10.13039\/501100000288","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MRC Cancer unit"}],"content-domain":{"domain":["royalsocietypublishing.org"],"crossmark-restriction":true},"short-container-title":["J. R. Soc. Interface."],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:p>\n                    During ageing, normal epithelial tissues progressively accumulate clones carrying mutations that increase mutant cell fitness above that of wild-type cells. Such mutants spread widely through the tissues, yet despite this cellular homeostasis and functional integrity of the epithelia are maintained. Two of the genes most commonly mutated in human skin and oesophagus are\n                    <jats:italic>p53<\/jats:italic>\n                    and\n                    <jats:italic>Notch1<\/jats:italic>\n                    , both of which are also recurrently mutated in cancers of these tissues. From observations taken in human and mouse epithelia, we find that clones carrying\n                    <jats:italic>p53<\/jats:italic>\n                    and\n                    <jats:italic>Notch<\/jats:italic>\n                    pathway mutations have different clone dynamics which can be explained by their different responses to local cell crowding.\n                    <jats:italic>p53<\/jats:italic>\n                    mutant clone growth in mouse epidermis approximates a logistic curve, but feedbacks responding to local crowding are required to maintain tissue homeostasis. We go on to show that the observed ability of\n                    <jats:italic>Notch<\/jats:italic>\n                    pathway mutant cells to displace the wild-type population in the mouse oesophageal epithelium reflects a local density feedback that affects both mutant and wild-type cells equally. We then show how these distinct feedbacks are consistent with the distribution of mutations observed in human datasets and are suggestive of a putative mechanism to constrain these cancer-associated mutants.\n                  <\/jats:p>","DOI":"10.1098\/rsif.2021.0607","type":"journal-article","created":{"date-parts":[[2021,10,12]],"date-time":"2021-10-12T20:02:05Z","timestamp":1634068925000},"update-policy":"https:\/\/doi.org\/10.1098\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Simulations reveal that different responses to cell crowding determine the expansion of\n                    <i>p53<\/i>\n                    and\n                    <i>Notch<\/i>\n                    mutant clones in squamous epithelia"],"prefix":"10.1098","volume":"18","author":[{"given":"Vasiliki","family":"Kostiou","sequence":"first","affiliation":[{"name":"Department of medical physics and biomedical engineering, UCL, Gower Street, London WC1E 6BT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2904-6902","authenticated-orcid":true,"given":"Michael W. J.","family":"Hall","sequence":"additional","affiliation":[{"name":"MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK"},{"name":"Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philip H.","family":"Jones","sequence":"additional","affiliation":[{"name":"MRC Cancer Unit, University of Cambridge, Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK"},{"name":"Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0355-2946","authenticated-orcid":true,"given":"Benjamin A.","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of medical physics and biomedical engineering, UCL, Gower Street, London WC1E 6BT, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"175","published-online":{"date-parts":[[2021,10,13]]},"reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature19768"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aau3879"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa6806"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0811-x"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1092"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05574"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1218835"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2009.12.016"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1239730"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15258-0"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.09.005"},{"key":"e_1_3_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2018.08.017"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2963"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0624-3"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2016.05.010"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10999"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3272"},{"key":"e_1_3_6_19_2","first-page":"G216","article-title":"Esophageal development and epithelial homeostasis","volume":"309","author":"Rosekrans SL","year":"2015","unstructured":"Rosekrans SL, Baan B, Muncan V, Van Den Brink GR. 2015 Esophageal development and epithelial homeostasis. Am. J. Physiol. 309, G216-228. (doi:10.1152\/ajpgi.00088.2015)","journal-title":"Am. J. 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