Elucidating the Cellular Origins of lung adenocarcinoma

肺癌是美国与癌症相关的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的临床表现为四大组织学 亚型(腺泡型、腺泡型、乳头型和实性)，有不同的EGFR和Kras突变表现 根据种族、年龄和性别，可以细分为四个不同的类别 全基因组DNA甲基化图谱。到目前为止，这些大相径庭的人之间几乎没有什么联系 LUAD的临床表现及其对患者总体生存的影响。在老鼠模型中有证据表明 提示LUAD大部分来源于肺表面活性蛋白C(Sftpc)阳性的肺泡上皮型 2(AT2)细胞，Scgb1a1阳性的俱乐部细胞也可在LUAD病例中贡献一小部分。然而， 目前尚不清楚LUAD是否起源于AT1细胞，AT1细胞是肺远端另一种主要的上皮细胞类型， 覆盖了95%的牙槽表面。AT1细胞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 KrasG12D在AT1细胞中的致癌驱动因素，并发现AT1细胞可以作为LUAD的起源细胞 以乳头状组织学为主，有明显的转录特征，包括 转化生长因子-β(TGFR-β)介导的上皮向间充质转化。这是在 与AT2细胞特异性的Sftpc驱动的KrasG12D形成对比，KrasG12D仅导致Lepitic LUAD，并 富含血管内皮生长因子介导的血管生成。因此，我们假设LUAD，按照目前的定义， 可能实际上是发生在远端牙槽的至少4种腺癌亚型的集合 以及我们在LUAD呈现和LUAD表现中看到的巨大差异 临床结果可以通过LUAD发生的细胞类型来部分解释。然而，有几个问题 留下来。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。我们会 因此(目标1)表征Gramd2-CreERT2驱动的EGFR突变，另一个主要致癌驱动因素 在LUAD。在AT1细胞中诱导KrasG12D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+谱系追踪以确定 体外和体内细胞对肿瘤形成的贡献。我们还将确定翻译的含义 我们之前的研究(目标3)，并利用转化生长因子β的抑制剂，已经在临床前模型中成功，但 在临床试验中未能确定来源细胞是否影响小鼠模型和 独特的人类LUAD患者队列。理解起源细胞与临床之间的联系 介绍将允许增强患者分层，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。

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.