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.

肺癌是美国最常见的癌症相关死亡原因， 腺癌（LUAD）是主要的组织学亚型。LUAD临床表现为四种主要的组织学改变， 亚型（麻风、腺泡、乳头状和实体），EGFR和Kras突变表现各异 根据种族、年龄和性别，可以分为四个独立的类别， 全基因组DNA甲基化图谱。迄今为止，这些大相径庭的 LUAD的临床表现，除了对患者总体生存率的影响。有证据表明， 提示大多数LUAD起源于表面活性蛋白c（Sftpc）阳性肺泡上皮型 2（AT 2）细胞，Scgb 1a 1阳性俱乐部细胞也可以贡献一小部分LUAD病例。但是，在这方面， 目前还不清楚LUAD是否可以由AT 1细胞产生，AT 1细胞是远端肺中的另一种主要上皮细胞类型， 覆盖95%的牙槽表面。AT 1细胞历来被认为是终末分化的。 然而，我们最近开发了一种Gramd 2驱动的CreERT 2小鼠模型， AT 1细胞中的KrasG 12 D致癌驱动因子，并发现AT 1细胞可以作为LUAD的起源细胞 主要是乳头状组织学和不同的转录组学特征，包括增加 转化生长因子β（TGF-β）介导的上皮细胞向间质细胞转化（EMT）。这是 与AT 2细胞特异性Sftpc驱动的KrasG 12 D相反，KrasG 12 D仅导致麻风LUAD， 富含VEGF介导的血管生成。因此，我们假设LUAD，正如目前定义的那样， 可能实际上是至少4种腺癌亚型的集合，这些腺癌亚型出现在远端肺泡 来自不同起源细胞的区室，我们在LUAD表达中看到的巨大变化， 临床结果可以部分地由LUAD产生的细胞类型来解释。然而，几个问题 保持。我们不知道AT 1细胞中的致癌驱动因子是否影响组织学表现。我们将 因此（目的1）表征Gramd 2-CreERT 2驱动的EGFR突变，另一个主要的致癌驱动因子 在LUAD。也有可能在AT 1细胞中诱导KrasG 12 D导致肿瘤破裂 因此，我们将（2）进行GFP+谱系追踪，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影响 我们先前的研究（目标3），并利用TGFβ抑制剂，已成功地在临床前模型，但 在临床试验中未能确定细胞来源是否影响两种小鼠模型对治疗的反应， 独特的人类患者LUAD群组。了解细胞起源与临床之间的联系 介绍将允许增强患者分层，改善对最佳治疗的评估， 结果，以及LUAD可能重新分类为多种癌症类型。