Patho-Genetic Analysis of Invasive Mucinous Adenocarcinoma of the Lung

尽管最近在分子靶向治疗和免疫治疗的发展方面取得了进展，但肺癌 仍然是癌症死亡的主要原因，因为这种疗法不适用于一半以上的肺癌 病人。肺腺癌是肺癌的主要病理类型。肺腺癌已经被 根据基因改变(例如，KRAS或EGFR突变和ALK融合)进一步细分 分化状态(包括腺泡型、淋巴管型、乳头状型、实性和粘液型等组织病理亚型)。 在大多数情况下，这种基因改变与肺的组织病理亚型没有严格的相关性。 腺癌。然而，导致侵袭性粘液细胞发展的遗传和分子途径 肺腺癌(IMA)是我们的团队和其他人在过去几年中发现的(例如， HNF4a途径)，提示这种分子途径可以靶向治疗有 目前还没有有效的治疗方法。值得注意的是，IMA的组织学与发现的产生粘液的癌症相似。 胃肠道(例如，胰腺癌)，这阻碍了从肺部正确诊断IMA的努力 源自其他产生粘液的器官的转移。一种区分IMA与肺的生物标志物 转移尚未确定。我们的长期目标是找到一种治疗IMA的方法。这里的目标是 以1)确定HNF4a及其下游基因是否在IMA中特异表达，但在IMA中未表达 正常肺可作为IMA的治疗靶点；2)全面确定治疗靶点， 使用新技术的生物标记物，如单细胞mRNA-seq和3D肿瘤样(器官)培养 大量的IMA标本(&gt；200)。中心假设是IMA是由不同的分子驱动的 可以作为治疗靶点的途径。理论基础是基于我们之前和初步的研究。 这表明1)HNF4a途径是IMA生长所必需的，2)这种途径产生了一种特定的 肿瘤微环境影响肿瘤相关细胞，呈现特定的治疗靶点和 生物标志物。这一假设将在以下具体目标中进行检验：1)确定HNF4a和/或 其下游基因可作为IMA的治疗靶点；2)单细胞分析IMA的异质性 3)发现IMA的诊断生物标志物。这种方法是创新的，因为它将专注于 尚未被探索为IMA治疗靶点的分子途径。拟议的研究将：1) 利用IMA模型小鼠(GEMM和PDX)和人的IMA和肺转移标本和2) 确定小分子抑制剂和治疗性抗体是否可以减少IMA的生长。这个 拟议的研究意义重大，因为我们的团队由来自几个国家的多名IMA研究人员组成 将把他们的知识和专业知识结合在一起，开发一种治疗IMA的新疗法。

Despite recent progress in the development of molecularly-targeted therapy and immunotherapy, lung cancer is still the leading cause of cancer death since such therapies are not applicable for more than half of lung cancer patients. Lung adenocarcinoma is the major pathological type of lung cancer. Lung adenocarcinoma has been further subdivided based on both genetic alterations (e.g., KRAS or EGFR mutations and ALK fusions) and differentiation state (including histopathologic subtypes such as acinar, lepidic, papillary, solid and mucinous). In most cases, such genetic alterations do not strictly correlate with the histopathologic subtypes of lung adenocarcinomas. However, genetic and molecular pathways that lead to the development of invasive mucinous adenocarcinoma of the lung (IMA) have been revealed by our team and others in the past several years (e.g., HNF4A pathway), suggesting that such molecular pathways can be targeted to treat IMA for which there is currently no effective therapy. Notably, the histology of IMA resembles that of mucus-producing cancers found in the gastrointestinal tract (e.g., pancreatic cancer), which hampers efforts to properly diagnose IMA from lung metastases originating from other mucus-producing organs. A biomarker to distinguish IMA from lung metastases has not been established. Our long-term goal is to identify a therapy for IMA. The objective here is to 1) determine whether HNF4A and its downstream genes that are specifically expressed in IMA but not in normal lung can be therapeutic targets for IMA and 2) comprehensively identify therapeutic targets and biomarkers using novel technologies such as single-cell mRNA-seq and 3D tumoroid (organoid) culture with a large number of IMA specimens (>200). The central hypothesis is that IMA is driven by distinct molecular pathways that can be therapeutically targeted. The rationale is based on our previous and preliminary studies indicating that 1) the HNF4A pathway is required for the growth of IMA and 2) such a pathway creates a specific tumor microenvironment that influences tumor-associated cells, which presents specific therapeutic targets and biomarkers. This hypothesis will be tested in the following specific aims: 1) determine whether HNF4A and/or its downstream genes can be therapeutic targets for IMA, 2) analyze the heterogeneity of IMA at a single-cell level, and 3) discover diagnostic biomarkers for IMA. The approach is innovative because it will focus on molecular pathways that have not been explored as therapeutic targets for IMA. The proposed research will: 1) utilize model mice for IMA (GEMM and PDX) and human specimens of IMA and lung metastases and 2) determine whether small molecular inhibitors and therapeutic antibodies can reduce the growth of IMA. The proposed research is significant because our team, comprised of a number of IMA researchers from several institutes, will bring their knowledge and expertise together to develop a novel therapy for IMA.