{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T14:06:39Z","timestamp":1790258799601,"version":"4.1.0"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004375","name":"Tel Aviv University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004375","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Anim Models and Exp Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Hepatocellular carcinoma is a leading cause of cancer\u2010related mortality worldwide.\n                    <jats:italic>Smad4<\/jats:italic>\n                    , a well\u2010established tumor suppressor within the transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) signaling pathway, has an oncogenic potential of its heterozygous loss, still poorly defined, especially across genetically diverse backgrounds. The aim was to investigate whether heterozygous loss of\n                    <jats:italic>Smad4<\/jats:italic>\n                    increases susceptibility to spontaneous liver tumor development in a genetically diverse murine population. We generated 260 F1(C57BL\/6J\/\n                    <jats:italic>Smad4<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    X CC) mice, including 131 females and 129 males, by crossing\n                    <jats:italic>Smad4<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    males (C57BL\/6J background) with females from 14 Collaborative Cross (CC) lines. Mice were maintained and monitored under standardized conditions for up to 80\u2009weeks. Liver tissues were analyzed by gross pathology and histology for evidence of neoplasia. Tumor incidence was calculated per CC line; and Fisher's exact tests were used to evaluate line\u2010specific susceptibility. Liver tumors developed in\n                    <jats:italic>Smad4<\/jats:italic>\n                    <jats:sup>+\/\u2212<\/jats:sup>\n                    mice (8\/260; 3.08%) background, with no tumors observed in wild\u2010type littermates. Four CC lines exhibited tumor\u2010positive, with elevated incidence in CC025 (15.79%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0011), CC010 (8.33%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0173), and CC005 (6.90%,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.0241). After Bonferroni correction for multiple comparisons, only CC025 remained statistically significant. Histopathology confirmed hepatocellular carcinoma in representative cases. Tumor incidence showed no sex bias and was restricted to specific genotypic contexts, indicating an interaction between heterozygous\n                    <jats:italic>Smad4<\/jats:italic>\n                    deletion and host genetic background. Partial loss of\n                    <jats:italic>Smad4<\/jats:italic>\n                    promotes liver carcinogenesis in a strain\u2010dependent manner, highlighting the importance of genetic modifiers in tumor susceptibility. The use of CC mice provides a valuable platform for uncovering genotype\u2010specific cancer susceptibilities in preclinical research.\n                  <\/jats:p>","DOI":"10.1002\/ame2.70283","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T13:42:26Z","timestamp":1790257346000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Developing a strain\u2010dependent susceptibility to hepatocellular carcinoma in a murine model based on histopathological evidence and genetic context"],"prefix":"10.1002","author":[{"given":"Osayd","family":"Zohud","sequence":"first","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Gray Faculty of Medicine and Health Sciences Tel\u2010Aviv University  Tel\u2010Aviv Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aysar","family":"Nashef","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Baruch Padeh Medical Center  Poriya Israel"},{"name":"Azrieli Faculty of Medicine Bar\u2010Ilan University  Ramat Gan Israel"},{"name":"Department of Oral and Maxillofacial Surgery Meir Medical Center, Affiliated to the Gray Faculty of Medicine and Health Sciences, Tel\u2010Aviv University  Kfar Saba Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Imad","family":"Abu\u2010Elnaaj","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery Baruch Padeh Medical Center  Poriya Israel"},{"name":"Azrieli Faculty of Medicine Bar\u2010Ilan University  Ramat Gan Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-206X","authenticated-orcid":false,"given":"Fuad A.","family":"Iraqi","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology and Immunology, Gray Faculty of Medicine and Health Sciences Tel\u2010Aviv University  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