Phenotype Interactions and Dynamics in SCLC Tumors

项目概要-项目2 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，这在很大程度上是因为SCLC肿瘤可以迅速对化疗产生耐药性。 化疗和放射治疗以及缺乏靶向治疗。新出现的证据支持 尽管SCLC肿瘤在显微镜下检查时似乎是同质的，但这些肿瘤 含有显著水平的肿瘤内异质性。事实上，我们小组和其他人最近的观察表明， 已经在SCLC中鉴定了不同的细胞表型，包括原发性人类肿瘤， 从人类肿瘤中，以及从基因工程小鼠模型中。重要的是，我们的数据 研究小组以及项目1的研究人员指出，这些细胞表型有助于小细胞肺癌 发展和对治疗的潜在反应。本提案的具体目标是阐明 SCLC肿瘤内的细胞亚群驱动SCLC动力学、生长、存活和侵袭性， 生态系统为了实现这一目标，我们将集中精力更好地了解SCLC表型的性质， 亚型以及这些群体在功能上如何相互作用以及与非癌细胞相互作用。 肿瘤微环境 具体来说，我们先前已经在SCLC肿瘤中鉴定了干细胞样肿瘤增殖细胞（TPC）， 发现这些细胞是神经内分泌的，并且具有很强的致瘤性。我们还描述了细胞 来源于这些具有不同表型的TPC的群体，包括非神经内分泌亚群 能促进神经内分泌TPC的生长和扩散。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，我们将使用 结合实验和数学方法来研究这些不同的SCLC细胞类型 有助于肿瘤生长，与肿瘤微环境有关。我们将建造和使用 数学建模预测具有不同表型的SCLC亚群之间的关键相互作用， 发现可用于治疗的脆弱性/干预点。建模也将是一个关键因素 驾驶实验设计作为该设计的一部分，我们将确定SCLC肿瘤中的细胞-细胞相互作用 影响不同亚群的分裂和存活率;我们还将确定表型 不同亚群之间的转换速率，以捕获SCLC动力学和可塑性。最后我们将 阐明这些SCLC亚群释放的分泌因子在驱动存活，生长， 表型组成和转移。这些实验将阐明 SCLC的发展和进展，并可能最终导致新的治疗方法，通过确定 SCLC亚群的关键相互作用。

PROJECT SUMMARY – PROJECT 2 Small Cell Lung Carcinoma (SCLC) is an aggressive neuroendocrine subtype of lung cancer. SCLC patients have a very low 5-year survival, in large part because SCLC tumors can become rapidly resistant to chemotherapy and radiation therapy and because of a lack of targeted therapies. 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 as well as from Project 1 investigators indicate that these cellular phenotypes contribute to SCLC development and potentially response to therapy. The specific goal of this proposal is to elucidate how different cellular subpopulations within SCLC tumors drive SCLC dynamics, growth, survival, and aggressiveness as an ecosystem. To accomplish this goal, we will focus on better understanding the nature of SCLC phenotypic subtypes and how these populations functionally interact with each other and with noncancerous cells in the tumor microenvironment. Specifically, we have previously identified stem-like 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 subpopulations that can promote the growth and the spread of the neuroendocrine TPCs. Leveraging these findings as well as our unique genetic mouse models that allow dissection of SCLC phenotype evolution, we will use a combination of experimental and mathematical approaches to investigate how these different SCLC cell types contribute to tumor growth, in relationship with the tumor microenvironment. We will build and use mathematical modeling to predict key interactions between SCLC subpopulations with distinct phenotypes and to uncover fragility/intervention points that could be used for treatment. Modeling will also be a key factor driving experimental design. As part of this design, we will determine how cell-cell interactions in SCLC tumors affect the division and survival rates of the different subpopulations; we will also determine phenotype transition rates between different subpopulations to capture SCLC dynamics and plasticity. Finally, we will elucidate the role of secretory factors released by these SCLC subpopulations in driving survival, growth, phenotype composition, and metastasis of SCLC tumors. These experiments will elucidate basic mechanisms of SCLC development and progression and may ultimately lead to novel therapeutic approaches by identifying key interactions of SCLC subpopulations.