Phenotype Interactions in SCLC Development and Detection

项目摘要 小细胞肺癌（SCLC）是一种侵袭性神经内分泌亚型的肺癌。SCLC 患者的5年生存率非常低，部分原因是SCLC肿瘤通常在晚期被发现， 肿瘤已经转移，治疗效果更差。因此，早期检测成为 这对于获得更好的治疗效果至关重要。新出现的证据支持这一观点，虽然SCLC肿瘤似乎 当在显微镜下检查时，这些肿瘤是均匀的， 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SCLC中，包括在原发性人肿瘤中，在来源于人肿瘤的细胞系中，和在来源于人肿瘤的肿瘤中， 基因工程小鼠模型。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。这项提案的具体目标是阐明不同的细胞如何 SCLC肿瘤内的亚群驱动早期SCLC发育、动力学和生长， 机制信息，以确定用于早期检测和预防SCLC的生物标志物。 我们先前已经鉴定了SCLC肿瘤中的肿瘤增殖细胞（TPC），并发现这些细胞 是神经内分泌和强烈的致瘤性。我们还表征了来自这些细胞的细胞群， 具有不同表型的TPC，包括非神经内分泌NOTCH+和CD 44+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 遗传小鼠模型，允许解剖SCLC表型进化，我们将研究细胞-细胞 这些不同的SCLC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。我们还将阐明分泌因子释放的作用，这些小细胞肺癌 亚群在驱动SCLC肿瘤的存活、生长和表型组成中的作用。最后我们将 分析SCLC患者血浆中存在的cfDNA和蛋白质（包括外来体）， 小细胞肺癌发生和早期检测相关标志物的鉴定。我们还将跟进耐人寻味的 NOTCH的生殖系突变存在于大部分SCLC患者中，这表明 潜在的危险因素除了吸烟。 这个跨学科的基本翻译项目将阐明SCLC的基本机制 开发和可能导致早期检测和/或预防SCLC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.