Phenotype Interactions and Dynamics in SCLC Tumors

SCLC 肿瘤的表型相互作用和动态

• 批准号: 10375423
• 负责人: Alissa M Weaver
• 金额: $ 42.03万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-13 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375423
• 关键词: Affect; Automobile Driving; Behavior; Biological Assay; Biology; Cell Communication; Cell Line; Cells; Chemotherapy and/or radiation; Communication; Complement; Complex; DNA Sequence Alteration; Data; Development; Disease; Dissection; Ecosystem; Epigenetic Process; Epithelial Cells; Evolution; Experimental Designs; Feedback; Generations; Genetic; Genetically Engineered Mouse; Goals; Growth; Heterogeneity; Human; In Vitro; Intervention; Knowledge; Lead; Lung; MYC Family Genes; Maintenance; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mesenchymal; Microscope; Modeling; Molecular; Mutation; Nature; Neoplasm Metastasis; Neuroendocrine Cell; Neuroendocrine Tumors; Neurosecretory Systems; PTEN gene; Patients; Phenotype; Population; Population Dynamics; Proteins; Publishing; Radiation therapy; Research Personnel; Resistance; Role; Supporting Cell; Survival Rate; System; Technology; Testing; Therapeutic Intervention; Transplantation; Tumor-Derived; Validation; Work; base; biological systems; cancer stem cell; cell type; design; experimental study; extracellular vesicles; human data; in silico; in vivo; lung small cell carcinoma; mathematical methods; mathematical model; mouse model; neoplastic cell; novel; novel therapeutic intervention; predictive modeling; release factor; release factor 3; response; self-renewal; single-cell RNA sequencing; stem; targeted treatment; tool; treatment response; tumor; tumor growth; tumor heterogeneity; tumor initiation; tumor microenvironment; tumor progression; tumorigenic; virtual

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.

项目摘要 - 项目2 小细胞肺癌（SCLC）是肺癌的侵略性神经内分泌亚型。 SCLC 患者的5年生存率非常低，在很大程度上是因为SCLC肿瘤可以迅速抵抗 化学疗法和放射疗法，并且由于缺乏靶向疗法。新兴证据支持 在显微镜下检查时SCLC肿瘤时，SCLC肿瘤似乎均匀的想法，但这些肿瘤 包含大量肿瘤内异质性。确实，我们小组和其他人的最新观察 在SCLC中鉴定了不同的细胞表型，包括原发性肿瘤，在衍生的细胞系中 来自人类肿瘤，以及遗传工程小鼠模型的肿瘤。重要的是，来自我们的数据 小组以及项目1研究者表明，这些细胞表型有助于SCLC 发展和对治疗的潜在反应。该提议的具体目标是阐明 SCLC肿瘤内的细胞亚群驱动SCLC动力学，生长，生存和侵略性作为一种 生态系统。为了实现这一目标，我们将专注于更好地理解SCLC表型的本质 亚型以及这些人群如何在功能上相互作用以及与非癌细胞相互作用 肿瘤微环境。 具体而言，我们以前已经鉴定出SCLC肿瘤中的干肿瘤传播细胞（TPC）和 发现这些细胞是神经内分泌和强烈肿瘤的。我们还表征了细胞 从这些具有不同表型的TPC得出的种群，包括非神经内分泌亚群 这可以促进神经内分泌TPC的生长和传播。利用这些发现以及 我们独特的遗传小鼠模型，允许解剖SCLC表型演化，我们将使用 实验和数学方法的结合，以研究这些不同的SCLC细胞类型如何 与肿瘤微环境关系有助于肿瘤生长。我们将建立和使用 数学建模，以预测SCLC亚群之间与不同表型和 发现可用于治疗的脆弱性/干预点。建模也将是关键因素 驾驶实验设计。作为此设计的一部分，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 不同亚种群之间的过渡速率捕获SCLC动力学和可塑性。最后，我们会的 阐明这些SCLC亚群释放的分泌因子在推动生存，生长， SCLC肿瘤的表型组成和转移。这些实验将阐明基本机制 SCLC的发展和进步，并最终通过识别来导致新的治疗方法 SCLC亚群的主要相互作用。