Novel murine primary and orthotopically nasopharyngeal cancer models reveal LMP1 as a driver of metastasis

Current NPC models cannot reproduce the process of NPC tumorigenesis, which is critical for investigating the functions and mechanisms of the disease-associated factors in this malignancy.So,we aimed to generate primary and orthotopic NPC models from normal nasopharyngeal epithelium with NPC related genetic drivers. For this purpose, we cultured normal mouse nasopharyngeal organoids and induced Trp53 and Cdkn2a mutations by CRISPR/cas9 editing, together with Myc overexpression. We showed that these organoids could initiate primary NPC once transplanted into recipient mice subcutaneously or orthotopically. And we also tested the functions of LMP1 in these models and found that it dramatically promoted NPC metastases. Overall design: Bulk RNA-seq of Normal nasopharyngeal organoids,Normal lung organoids; Trp53-/-;Myc;sgCdkn2a primary and metastasized tumor organoids, and Trp53-/-;Myc;sgCdkn2a; LMP1 primary and metastasized tumor organoids

当前的鼻咽癌（Nasopharyngeal Carcinoma, NPC）模型无法复现鼻咽癌的肿瘤发生过程，而该过程对于研究该恶性肿瘤中疾病相关因子的功能与作用机制至关重要。为此，本研究旨在从正常鼻咽上皮出发，结合鼻咽癌相关遗传驱动因子，构建原发性及原位鼻咽癌模型。具体而言，我们培养了正常小鼠鼻咽类器官，并通过CRISPR/Cas9编辑引入Trp53与Cdkn2a突变，同时实现Myc过表达。实验结果表明，将此类类器官移植至受体小鼠皮下或原位后，可诱发原发性鼻咽癌。此外，我们在该模型中验证了潜伏膜蛋白1（Latent Membrane Protein 1, LMP1）的功能，发现其可显著促进鼻咽癌转移。整体实验设计：对正常鼻咽类器官、正常肺类器官；携带Trp53敲除、Myc过表达及sgCdkn2a编辑的原发性与转移性肿瘤类器官，以及携带Trp53敲除、Myc过表达、sgCdkn2a编辑并过表达LMP1的原发性与转移性肿瘤类器官进行批量RNA测序（Bulk RNA-seq）。