Phenotype Interactions in SCLC Development and Detection

项目总结 小细胞肺癌(SCLC)是一种侵袭性的神经内分泌亚型肺癌。小细胞肺癌 患者的5年存活率非常低，部分原因是小细胞肺癌肿瘤通常在晚期才被发现 肿瘤已经转移，治疗结果更糟。因此，及早发现成为 对于取得更好的治疗效果至关重要。新出现的证据支持这样一种观点，尽管小细胞肺癌肿瘤似乎 均质在显微镜下观察，这些肿瘤含有大量的瘤内组织。 异质性。事实上，我们小组和其他人最近的观察已经确定了不同的细胞表型 在小细胞肺癌中，包括在原发的人类肿瘤中，在来自人类肿瘤的细胞系中，在来自 转基因小鼠模型。重要的是，我们小组的数据表明，这些细胞表型 为SCLC的发展做出贡献。这项提议的具体目标是阐明不同的细胞 小细胞肺癌肿瘤内的亚群推动早期小细胞肺癌的发展、动态和生长，并利用这一点 为早期发现和预防小细胞肺癌识别生物标志物提供机械信息。 我们之前已经在小细胞肺癌肿瘤中发现了肿瘤增殖细胞(TPC)，并发现这些细胞 是神经内分泌和强烈的致癌作用。我们还对源自这些细胞的细胞群体进行了表征 具有不同表型的TPC，包括非神经内分泌Noch+和CD44+亚群， 促进神经内分泌TPC的生长和存活。利用这些发现以及我们独特的 小鼠遗传模型允许解剖小细胞肺癌的表型进化，我们将研究细胞-细胞 这些不同的小细胞肺癌细胞表型的相互作用有助于肿瘤的发展和生长 与肿瘤微环境的关系。我们还将阐明这些小细胞肺癌释放的分泌因子的作用。 亚群在小细胞肺癌生存、生长和表型组成中的作用。最后，我们会 对小细胞肺癌患者血浆中存在的cfDNA和蛋白质(包括外切体)进行分析 小细胞肺癌发生的相关标志物鉴定及早期发现。我们还将跟进有趣的 研究发现，在很大一部分小细胞肺癌患者中存在Noch的胚系突变，这表明 吸烟以外的潜在风险标记物。 这项跨学科的基础-翻译项目将阐明小细胞肺癌的基本机制 发展，并可能导致早期发现和/或预防小细胞肺癌的新方法。

PROJECT SUMMARY Small Cell Lung Carcinoma (SCLC) is an aggressive neuroendocrine subtype of lung cancer. SCLC patients have a very low 5-year survival, in part because SCLC tumors are often detected at a late stage when the tumors have already metastasized and treatment outcomes are worse. Thus, early detection becomes critical to achieve better treatment results. Emerging evidence supports the idea that, while SCLC tumors seem homogeneous when examined under a microscope, these tumors contain a significant level of intra-tumoral heterogeneity. Indeed, recent observations by our group and others have identified distinct cellular phenotypes in SCLC, including in primary human tumors, in cell lines derived from human tumors, and in tumors from genetically-engineered mouse models. Importantly, data from our group indicate that these cellular phenotypes contribute to SCLC development. The specific goal of this proposal is to elucidate how different cellular subpopulations within SCLC tumors drive early SCLC development, dynamics, and growth and to leverage this mechanistic information to identify biomarkers for early detection and prevention of SCLC. We have previously identified tumor-propagating cells (TPCs) in SCLC tumors and found that these cells are neuroendocrine and strongly tumorigenic. We have also characterized cell populations derived from these TPCs with distinct phenotypes, including non-neuroendocrine NOTCH+ and CD44+ subpopulations, that promote the growth and survival of the neuroendocrine TPCs. Leveraging these findings as well as our unique genetic mouse models that allow dissection of SCLC phenotype evolution, we will investigate how cell-cell interactions of these distinct SCLC cell phenotypes contribute to tumor development and growth, in relationship with the tumor microenvironment. We will also elucidate the role of secretory factors released by these SCLC subpopulations in driving survival, growth, and phenotype composition of SCLC tumors. Finally, we will perform analysis of cfDNA and proteins (including on exosomes) present in SCLC patient plasma for identification of related markers of SCLC development and early detection. We will also follow up on intriguing findings that germline mutations in NOTCH are present in a large fraction of SCLC patients, suggesting a potential risk marker beyond smoking. This interdisciplinary basic-translational project will elucidate fundamental mechanisms of SCLC development and may lead to novel methods for early detection and/or prevention of SCLC.