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，很大程度上是因为小细胞肺癌肿瘤可以迅速对 化疗和放射治疗，以及缺乏有针对性的治疗。新出现的证据支持 虽然小细胞肺癌肿瘤在显微镜下检查时看起来是均匀的，但这些肿瘤 包含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到 在小细胞肺癌中发现了不同的细胞表型，包括在人类原发肿瘤中，在衍生的细胞系中 来自人类肿瘤，以及来自基因工程小鼠模型的肿瘤。重要的是，来自我们的数据 研究小组和项目1的研究人员表明，这些细胞表型对小细胞肺癌有贡献 发展和潜在的治疗反应。这项提议的具体目标是阐明 小细胞肺癌肿瘤内的细胞亚群推动小细胞肺癌的动态、生长、存活和侵袭性 生态系统。为了实现这一目标，我们将专注于更好地理解小细胞肺癌表型的性质。 亚型以及这些群体如何在功能上相互作用以及如何与非癌细胞相互作用 肿瘤微环境。 具体地说，我们以前在小细胞肺癌肿瘤和小细胞肺癌中发现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，具有很强的致瘤性。我们还对细胞进行了表征 来自这些具有不同表型的TPC的群体，包括非神经内分泌亚群 这可以促进神经内分泌TPC的生长和扩散。利用这些发现以及 我们独特的小鼠遗传模型允许解剖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细胞类型如何 促进肿瘤生长，与肿瘤微环境有关。我们将建造并使用 用数学模型预测具有不同表型的小细胞肺癌亚群与 以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 推动实验设计。作为这项设计的一部分，我们将确定小细胞肺癌肿瘤中细胞与细胞的相互作用 影响不同亚群的分裂和存活率；我们还将确定表型 不同亚群之间的过渡率，以捕捉小细胞肺癌的动态和可塑性。最后，我们会 阐明这些小细胞肺癌亚群释放的分泌因子在推动生存、生长、 小细胞肺癌肿瘤的表型组成和转移。这些实验将阐明基本的机制。 小细胞肺癌的发展和进展，并可能最终导致新的治疗方法通过识别 小细胞肺癌亚群的关键交互作用。