Intercepting progression from pre-invasive to invasive lung adenocarcinoma

摘要 尽管治疗策略取得了进展，但非小细胞肺癌仍然是一种致命的疾病。一个 需要对肺癌的生物学有更好的了解，以便在早期就能阻止这种疾病， 它的进展。我们的项目，这是由这一挑战的启发，重点是在最早的事件发生 肺癌的放射学检测表现：计算机断层扫描（CT）检测到的非 实性结节，其中多达40%含有明显浸润性腺癌。因此，尽管传统的 CT检测到的非实性结节代表了早期或微创恶性肿瘤， 更多的侵袭性组织学发生在这些结节的显著比例中。 了解非实性结节内推动进展的细胞和分子变化将提供 对肺癌发生的基本机制的独特和新颖的见解。我们假设 肿瘤微环境（TME）细胞的改变在启动和支持这一过程中起作用。 进展与该提议一致，我们初步的多重免疫荧光（IF）研究 表明向更具侵袭性表型的进展与强的 免疫抑制性TME。在这个项目中，我们使用多维方法来测试我们的假设， TME，并确定癌细胞和TME之间的串扰，在浸润前到浸润的人 肺非实性腺癌。与肿瘤相关的细胞和分子事件的比较分析 不同的组织学阶段将导致识别触发进展的关键事件， 从而鉴定阻断疾病进展的靶点。我们将在临床前使用适当的小鼠模型 研究开发这些目标作为策略，以阻止浸润前癌症向浸润性癌症的进展。 在这些研究的第一阶段（UG3阶段），我们将定义与肿瘤进展相关的TME改变。 在研究中使用RNAseq分析和基于图像的方法（多重IF和成像CyTOF） 我们的肿瘤样本档案这些研究将产生一个全面的细胞和 触发惰性病变进展为明显浸润性癌症的分子事件，具有强烈的焦点 关于免疫机制。这些分析将提供新的和详细的见解如何组成 并且TME的活性随着进展而变化。在第二阶段（UH3阶段），我们将利用鼠标 模型，以探索针对免疫机制和预防进展的拦截策略。 拟议队列满足RFA对癌症免疫预防研究高风险队列的关注， 因为肺结节是吸烟者中高度流行的癌前病变。

Abstract Despite advances in therapeutic strategies, non-small cell lung cancer remains a deadly disease. An improved understanding of the biology of lung cancer is needed to intercept the disease at an early point in its progression. Our project, which is inspired by that challenge, focuses on events transpiring in the earliest radiographically-detected manifestation of lung cancer: the computerized tomography (CT)-detected non- solid nodule, of which as many as 40% harbor frankly invasive adenocarcinoma. Thus, despite conventional wisdom that CT-detected non-solid nodules represent pre or minimally invasive malignancy, clearly transition to more invasive histologies occurs in a significant proportion of these nodules. Understanding the cellular and molecular changes within non-solid nodules that drive progression will provide unique and novel insights into the fundamental mechanisms of lung carcinogenesis. We hypothesize that alterations in cells of the tumor microenvironment (TME) have a role in initiating and supporting this progression. In agreement with that proposal, our preliminary multiplex immunofluorescence (IF) studies suggest that progression to a more invasive phenotype is associated with the development of a strong immunosuppressive TME. In this project we test our hypothesis using multidimensional methods to profile the TME and to determine the crosstalk between cancer cells and the TME in pre-invasive to invasive human lung non-solid adenocarcinomas. Comparative analysis of the cellular and molecular events associated with the distinct histological stages will lead to identification of the critical events triggering progression and thereby identify targets to intercept disease progression. We will use appropriate mouse models in pre-clinical studies to develop these targets as strategies to intercept progression of pre-invasive to invasive cancer. In the first phase of these studies (UG3 phase), we will define TME alterations associated with progression of lung nodules using RNAseq profiling and image-based methods (multiplex IF and imaging CyTOF) in studies of our archival tumor samples. These studies will generate a comprehensive catalogue of the cellular and molecular events that trigger progression of indolent lesions to frankly invasive cancers, with a strong focus on immune mechanisms. These analyses will provide novel and detailed insights into how the composition and activity of the TME changes with progression. In the second phase (UH3 phase), we will leverage mouse models to explore interception strategies to target immune mechanisms and prevent progression. The proposed cohort satisfies the RFA’s focus on High-Risk Cohorts for Cancer-Immunoprevention Studies, since lung nodules are premalignancies highly prevalent in smokers.