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It is frequently associated with Epstein\u2010Barr virus (EBV) infection, while there are also some NPC patients without EBV infection. Here, it is shown that the EBV+ (EBV positive) and EBV\u2010 (EBV negative) NPCs contain both shared and distinct genetic abnormalities, among the latter are increased mutations in\n                    <jats:italic>TP53<\/jats:italic>\n                    . To investigate the functional roles of NPC\u2010associated genetic alterations, primary, orthotopic, and genetically defined NPC models were developed in mice, a key tool missed in the field. These models, initiated with gene\u2010edited organoids of normal nasopharyngeal epithelium, faithfully recapitulated the pathological features of human disease. With these models, it is found that\n                    <jats:italic>Trp53<\/jats:italic>\n                    and\n                    <jats:italic>Cdkn2a<\/jats:italic>\n                    deficiency are crucial for NPC initiation and progression. And latent membrane protein1 (LMP1), an EBV\u2010coding oncoprotein, significantly promoted the distal metastasis. Further, loss of\n                    <jats:italic>TGFBR2<\/jats:italic>\n                    , which is frequently disrupted both in EBV\u2010 and EBV+ NPCs, dramatically accelerated the progression and lung metastasis of NPC probably by altering tumor microenvironment. Taken together, this work establishes a platform to dissect the genetic mechanisms underlying NPC pathogenesis and might be of value for future translational studies.\n                  <\/jats:p>","DOI":"10.1002\/advs.202403161","type":"journal-article","created":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T03:56:50Z","timestamp":1721879810000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Primary and Orthotopic Murine Models of Nasopharyngeal Carcinoma Reveal Molecular Mechanisms Underlying its Malignant Progression"],"prefix":"10.1002","volume":"11","author":[{"given":"Xudong","family":"Wan","sequence":"first","affiliation":[{"name":"Division of Thoracic Tumor Multimodality Treatment State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University  Chengdu Sichuan 610041 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