Faithful mouse modeling of human lung cancer

摘要 肺癌是男性和女性癌症相关死亡的主要原因，5年存活率高。 只有19%。尽管PD-1免疫检查点阻断疗法可能会改善这些结果，但大多数 的肺癌患者仍然未能通过这种创新的免疫疗法。肺癌领域的一个主要障碍是 缺乏可靠的模型，适合于确定潜在的启动和进展机制，以及 目的是研究人类肺癌的转移情况，并测试针对这一头号癌症杀手的新治疗策略。 使用已建立的癌细胞系的异种移植、同基因或人源化小鼠模型不能概括 癌症和间质细胞的自然协同进化以及它们在复杂的微观结构中的复杂相互作用 环境。此外，使用免疫低下的小鼠进行异种移植排除了关键的 癌细胞和免疫系统之间的相互作用。为了迎接这一重要挑战，我们最近 建立了一种新的小鼠肺癌模型，其过程从肿瘤起始到局部和 远处转移的外显率为100%。值得注意的是，内源性肺癌的转移模式 模型与患者的人类模型非常相似。在本应用程序中，我们将系统地 描述这个模型，重要的是，检查它是否在分子上、基因上复制了人类肺癌 和免疫表型。我们还将建立几个互补的模型，并将它们与 成像标志物荧光素酶和增强型绿色荧光蛋白(EGFP)允许监测和 在体内无创追踪肿瘤的发展和转移。这些研究将建立可靠的模型 并提供有关人类肺癌的基础知识。它们对癌症领域也具有重要意义。 总的来说，鉴于目前对癌症的了解有限，特别是从肿瘤开始的整个过程 一般为区域性和远处转移。

Abstract Lung cancer is the leading cause of cancer-related deaths in both men and women with a 5-year survival rate of only 19%. Although PD-1 immune checkpoint blockade therapy may improve these outcomes, the majority of lung cancer patients still fail this innovative immunotherapy. One major obstacle in the lung cancer field is the lack of faithful models that are suitable to identify mechanisms underlying the initiation and progression and metastasis of human lung cancer and to test new therapeutic strategies against this number 1 cancer killer. Xenograft, syngeneic or humanized mouse models using established cancer cell lines cannot recapitulate the natural coevolution of cancer and stromal cells as well as their intricate interplay in the complex micro- environment. Furthermore, using immunocompromised mice for xenograft transplants precludes the critical interaction between cancer cells and the immune system. To meet this important challenge, we have recently generated a novel mouse model of lung cancer, with the full process from tumor initiation to regional and distant metastasis at a penetrance of 100%. Notably, the metastasis pattern in this endogenous lung cancer model closely resembles that of its human counterpart in patients. In this application we will systematically characterize this model, and importantly, examine if it replicates human lung cancer molecularly, genetically and immuno-phenotypically. We will also establish several complementary models and incorporate them with the imaging markers luciferase and enhanced green fluorescent protein (EGFP) allowing monitoring and tracking tumor development and metastasis non-invasively in vivo. These studies will establish faithful models and provide fundamental knowledge on human lung cancer. They are also highly significant to the cancer field at large, given the currently limited knowledge on cancer, and in particular, the full process from tumor initiation to regional and distant metastasis in general.