{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:23:54Z","timestamp":1772173434659,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012915","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000}}],"reference-count":91,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100002086","name":"Fanconi Cancer Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100002086","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["1DP2CA280623"],"award-info":[{"award-number":["1DP2CA280623"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Fanconi Anemia (FA) is a heritable syndrome characterized by DNA damage repair deficits, frequent malformations and a significantly elevated risk of bone marrow failure, leukemia, and mucosal head and neck squamous cell carcinomas (HNSCC). Hematopoietic stem cell gene therapy can prevent marrow failure and lower leukemia risk, but mucosal gene therapy to lower HNSCC risk remains untested. Major knowledge gaps include an incomplete understanding of how rapidly gene-corrected cellular lineages could spread through the oral epithelium, and which delivery parameters are critical for ensuring efficient gene correction. To answer these questions, we extended an agent-based model of the oral epithelium to include the delivery of gene correction\n                    <jats:italic>in situ<\/jats:italic>\n                    to FA cells and determine the competitive dynamics between cellular lineages with and without gene correction. We found that only gene-corrected lineages with substantial proliferative advantages (probability of resisting displacement out of the basal layer\n                    <jats:inline-formula id=\"pcbi.1012915.e001\">\n                      <jats:alternatives>\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" id=\"pcbi.1012915.e001g\" mimetype=\"image\" position=\"anchor\" xlink:href=\"info:doi\/10.1371\/journal.pcbi.1012915.e001\" xlink:type=\"simple\"\/>\n                        <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\" display=\"inline\" id=\"M1\">\n                          <mml:mrow>\n                            <mml:mo>\u2265<\/mml:mo>\n                            <mml:mrow>\n                              <mml:mtext>0<\/mml:mtext>\n                            <\/mml:mrow>\n                            <mml:mo>.<\/mml:mo>\n                            <mml:mrow>\n                              <mml:mtext>1<\/mml:mtext>\n                            <\/mml:mrow>\n                          <\/mml:mrow>\n                        <\/mml:math>\n                      <\/jats:alternatives>\n                    <\/jats:inline-formula>\n                    ) could spread on clinically relevant timelines, and that these lineages were initially at high risk of loss in the generations following correction. Delivering gene correction to many cells minimizes the risk of loss, while delivery to many distinct locations within a tissue maximizes the rate of spread. To determine the impact of mucosal gene therapy in preventing the clonal expansion of pre-cancerous mutations, we compared the expected burden of\n                    <jats:italic>TP53<\/jats:italic>\n                    mutations in simulated tissue sections with and without gene correction. We found that when FA cells have elevated genome instability or a\n                    <jats:italic>TP53<\/jats:italic>\n                    -dependent proliferative advantage, gene correction can substantially reduce the accumulation of pro-tumorigenic mutations. This model illustrates the power of computational frameworks to identify critical determinants of therapeutic success to enable experimental optimization and support novel and effective gene therapy applications.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1012915","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T17:50:47Z","timestamp":1757526647000},"page":"e1012915","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epithelial competition determines gene therapy potential to suppress Fanconi Anemia oral cancer risk"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6660-8460","authenticated-orcid":true,"given":"Hunter L.","family":"Colegrove","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7638-7393","authenticated-orcid":true,"given":"Raymond J.","family":"Monnat Jr.","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2915-089X","authenticated-orcid":true,"given":"Alison F.","family":"Feder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"pcbi.1012915.ref001","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1146\/annurev-cancerbio-030617-050422","article-title":"The Fanconi Anemia Pathway in Cancer","volume":"3","author":"J Niraj","year":"2019","journal-title":"Annual Review of Cancer Biology"},{"issue":"7","key":"pcbi.1012915.ref002","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/nrc3088","article-title":"DNA interstrand crosslink repair and cancer","volume":"11","author":"AJ Deans","year":"2011","journal-title":"Nat Rev Cancer"},{"issue":"3","key":"pcbi.1012915.ref003","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1038\/nrc.2017.116","article-title":"Fanconi anaemia and cancer: an intricate relationship","volume":"18","author":"G Nalepa","year":"2018","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"pcbi.1012915.ref004","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/s41572-020-00224-3","article-title":"Head and neck squamous cell carcinoma","volume":"6","author":"DE Johnson","year":"2020","journal-title":"Nat Rev Dis Primers"},{"issue":"1","key":"pcbi.1012915.ref005","doi-asserted-by":"crossref","first-page":"30","DOI":"10.3324\/haematol.2017.178111","article-title":"Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up","volume":"103","author":"BP Alter","year":"2018","journal-title":"Haematologica"},{"key":"pcbi.1012915.ref006","doi-asserted-by":"crossref","unstructured":"Velleuer E, Dom\u00ednguez-H\u00fcttinger E, Rodr\u00edguez A, Harris LA, Carlberg C. 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