Elucidating the Cellular Origins of lung adenocarcinoma

阐明肺腺癌的细胞起源

基本信息

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
项目类别：
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

项目摘要

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.

肺癌是美国癌症相关死亡人数最多的原因，而肺癌腺癌（LUAD）是主要的组织学亚型，LUAD在临床上呈现四种主要的组织学类型。亚型（鳞状、腺泡状、乳头状和实性），具有不同的 EGFR 和 Kras 突变表现根据种族、年龄和性别，可分为四个不同的类别迄今为止，这些截然不同的基因组 DNA 甲基化谱之间几乎没有联系。 LUAD 的表现除了对患者总体生存的影响之外，还有小鼠模型的证据。表明大多数 LUAD 源自表面活性剂蛋白 c (Sftpc) 阳性肺泡上皮类型 2 (AT2) 细胞，Scgb1a1 阳性俱乐部细胞也可能导致 LUAD 病例的一小部分。目前尚不清楚 LUAD 是否可以由 AT1 细胞产生，AT1 细胞是远端肺中另一种主要的上皮细胞类型， AT1 细胞覆盖了 95% 的肺泡表面，历来被认为是终末分化的。然而，我们最近开发了一种 Gramd2 驱动的 CreERT2 小鼠模型，该模型专门激活 AT1细胞中的KrasG12D致癌驱动因素，并发现AT1细胞可以作为LUAD的起源细胞具有主要的乳头状组织学和独特的转录组特征，包括增加转化生长因子β（TGF-β）介导的上皮间质转化（EMT）。与 AT2 细胞特异性 Sftpc 驱动的 KrasG12D 相比，KrasG12D 仅导致鳞状 LUAD，并且因此，我们追求目前定义的 LUAD，实际上可能是至少 4 种出现在远端肺泡的腺癌亚型的集合来自不同来源细胞的区室，并且我们在 LUAD 呈现和中看到的巨大差异临床结果可以部分地通过 LUAD 出现的细胞类型来解释。但是，有几个问题；我们不知道 AT1 细胞中的致癌驱动因素是否会影响组织学表现。因此（目标 1）表征 Gramd2-CreERT2 驱动的 EGFR 突变，这是另一个主要的致癌驱动因素在 LUAD 中，AT1 细胞中 KrasG12D 的诱导也可能导致肿瘤破裂。因此，我们将 (2) 进行 GFP+ 谱系追踪以确定我们还将确定体外和体内细胞对肿瘤形成的影响。我们之前的研究（目标 3）并利用已在临床前模型中取得成功的 TGFβ 抑制剂，但在临床试验中未能确定起源细胞是否影响小鼠模型和小鼠模型对治疗的反应独特的人类患者 LUAD 队列了解细胞起源与临床之间的联系。演示将有助于加强患者分层，改进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。