Elucidating the Cellular Origins of lung adenocarcinoma

阐明肺腺癌的细胞起源

• 批准号: 10743611
• 负责人: Crystal Nicole Marconett
• 金额: $ 49.42万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-11 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10743611
• 关键词: Adenocarcinoma; Affect; Age; Air Sacs; Alveolar; Architecture; Cancerous; Categories; Cell Differentiation process; Cell Line; Cell Nucleus; Cells; Cessation of life; Classification; Clinical; Clinical Trials; Collection; DNA Methylation; Data; Development; Diagnosis; Disease; Disparate; Distal; Epidermal Growth Factor Receptor; Epithelial Cells; Epithelium; Ethnic Origin; Event; Exhibits; Gases; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Green Fluorescent Proteins; Heterogeneity; Histologic; Histology; Human; In Vitro; KRAS2 gene; KRASG12D; Label; Light; Lung; Lung Adenocarcinoma; MADH3 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Monoclonal Antibodies; Morphology; Mus; Mutation; Neoplasm Metastasis; Oncogenic; Outcome; Papillary; Pathologic; Patients; Phenotype; Population; Pre-Clinical Model; Prevention; Proteins; Pulmonary Surfactant-Associated Protein C; Research; Resistance; Role; Scanning; Solid; Surface; Therapy Evaluation; Transforming Growth Factor Beta 2; Transforming Growth Factor beta; Transgenic Mice; Translating; Transplantation; Tumor-Derived; United States; Variant; Vascular Endothelial Growth Factors; X-Ray Computed Tomography; alveolar epithelium; angiogenesis; cancer cell; cancer type; cell type; cohort; driver mutation; effectiveness evaluation; epithelial to mesenchymal transition; genome-wide; improved; in vivo; in vivo evaluation; inhibitor; microCT; mouse model; mutant; never smoker; novel therapeutic intervention; patient expectation; patient population; patient stratification; preclinical evaluation; promoter; response; sex; small molecule inhibitor; surfactant; therapy outcome; transcriptomic profiling; transcriptomics; treatment response; treatment strategy; tumor; tumor microenvironment

Lung cancer is responsible for the most cancer-related deaths in the United States, and Lung adenocarcinoma (LUAD) is the major histologic subtype. LUAD presents clinically with four major histologic subtypes (lepidic, acinar, papillary and solid), has variable presentation of EGFR and Kras mutations depending on ethnicity, age, and sex, and can be subclassified into four separate categories based on genome-wide DNA methylation profiles. To date, there is little connection between these widely disparate manifestations of LUAD besides their effects on overall patient survival. There is evidence in mouse models to suggest that the majority of LUAD arise from surfactant protein c (Sftpc)-positive alveolar epithelial type 2 (AT2) cells, and that Scgb1a1-positive club cells can also contribute a fraction of LUAD cases. However, it is unknown if LUAD can arise from AT1 cells, the other major epithelial cell type in the distal lung that covers 95% of the alveolar surface. AT1 cells were historically thought to be terminally differentiated. However, we have recently developed a Gramd2-driven CreERT2 mouse model that specifically activated the KrasG12D oncogenic driver in AT1 cells, and found that AT1 cells can serve as a cell of origin for LUAD with predominantly papillary histology and distinct transcriptomic signatures, including increased transforming growth factor beta (TGF-β)-mediated epithelial to mesenchymal transition (EMT). This is in contrast to AT2 cell-specific Sftpc-driven KrasG12D, which resulted exclusively in lepidic LUAD and was enriched for VEGF-mediated angiogenesis. Therefore, we hypothesize that LUAD, as it is currently defined, may actually be a collection of at least 4 adenocarcinoma subtypes that arise in the distal alveolar compartment from different cells of origin, and that the great variation we see in LUAD presentation and clinical outcome can be explained in part by which cell type LUAD arises in. However; several questions remain. We do not know if the oncogenic driver in AT1 cells influences histologic presentation. We will therefore (Aim 1) characterize Gramd2-CreERT2 driven EGFR mutations, the other major oncogenic driver in LUAD. It is also possible that induction of KrasG12D in AT1 cells results in disrupted tumor microenvironments that stimulate AT2 cells; we will therefore (2) perform GFP+ lineage tracing to determine in vitro and in vivo cell contributions to tumor formation. We will also establish the translational implications of our prior research (Aim 3) and utilize inhibitors of TGFβ that have succeeded in preclinical models but failed in clinical trials to determine if cell of origin influences response to therapy in both mouse models and unique human patient LUAD cohorts. Understanding the connection between cell of origin and clinical presentation will allow for enhanced patient stratification, improved assessment of best therapeutic outcomes, and potential reclassification of LUAD into multiple cancer types.

肺癌导致美国与癌症最相关的死亡，肺癌 腺癌（LUAD）是主要的组织学亚型。 Luad在临床上呈现四个主要的组织学 亚型（Lepidic，腺泡，乳头状和固体）具有EGFR和KRAS突变的变化 取决于种族，年龄和性别，可以根据种族，年龄和性别分类为四个单独的类别 全基因组DNA甲基化谱。迄今为止，这些广泛的不同 LUAD的表现外，除了它们对整体患者生存的影响。鼠标模型中有证据 提示大多数LUAD来自表面活性剂蛋白C（SFTPC） - 阳性肺泡上皮类型 2（AT2）细胞，SCGB1A1阳性俱乐部细胞也可以贡献一部分LUAD病例。然而， 未知是否可以来自AT1细胞，AT1细胞是圆盘肺中的另一种主要上皮细胞类型 覆盖肺泡表面的95％。历史上，AT1细胞被认为是终极分化的。 但是，我们最近开发了一个由GRAMD2驱动的Creert2小鼠模型，该模型专门激活 AT1细胞中的Krasg12d致癌驱动器，发现AT1细胞可以用作LUAD的原始细胞 主要是乳头状组织学和不同的转录组特征，包括增加 转化生长因子β（TGF-β）介导的上皮到间充质转变（EMT）。这是 与AT2细胞特异性SFTPC驱动的KRASG12D形成鲜明对比，后者仅产生LEPIDIC LUAD，为 富含VEGF介导的血管生成。因此，我们假设luad当前定义， 实际上，可能是至少4个腺癌亚型的集合 来自不同原始细胞的隔间，以及我们在LUAD呈现中看到的巨大变化和 临床结果可以在某种程度上通过哪种细胞类型的形式解释。几个问题 保持。我们不知道AT1细胞中的致癌驱动力是否会影响组织学表现。我们将 因此（AIM 1）表征GRAMD2-CREERT2驱动的EGFR突变，这是另一个主要的致癌驱动器 在卢德。 AT1细胞中KRASG12D的诱导也可能导致肿瘤破坏 刺激AT2细胞的微环境；因此，我们将（2）执行GFP+谱系跟踪以确定 体外和体内细胞对肿瘤形成的贡献。我们还将建立翻译的含义 我们先前的研究（AIM 3）并利用在临床前模型中成功但 在临床试验中失败以确定起源细胞是否影响小鼠模型和 独特的人类患者luad队列。了解原点和临床细胞之间的联系 演示将允许增强患者分层，改进对最佳治疗的评估 结果，并将LUAD的潜在重新分类为多种癌症类型。