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）是肺癌的一种侵袭性神经内分泌亚型。小细胞肺癌 患者的 5 年生存率非常低，很大程度上是因为 SCLC 肿瘤可以迅速对药物产生耐药性 化疗和放射治疗以及缺乏靶向治疗。新出现的证据支持 该观点认为，虽然 SCLC 肿瘤在显微镜下检查时看起来是同质的，但这些肿瘤 包含显着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 已经鉴定出 SCLC 中不同的细胞表型，包括原发性人类肿瘤、衍生的细胞系 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 小组以及项目 1 的研究人员表明这些细胞表型有助于 SCLC 发育和对治疗的潜在反应。该提案的具体目标是阐明如何不同 SCLC 肿瘤内的细胞亚群驱动 SCLC 动态、生长、存活和侵袭性 生态系统。为了实现这一目标，我们将重点更好地了解 SCLC 表型的本质 亚型以及这些群体如何在功能上彼此相互作用以及与体内的非癌细胞相互作用 肿瘤微环境。 具体来说，我们之前已经在 SCLC 肿瘤和 发现这些细胞具有神经内分泌细胞和强致瘤性。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 可以促进神经内分泌TPC的生长和扩散。利用这些发现以及 我们独特的基因小鼠模型可以剖析 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 有助于肿瘤生长，与肿瘤微环境有关。我们将建造并使用 数学模型来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。造型也将是一个关键因素 驱动实验设计。作为该设计的一部分，我们将确定 SCLC 肿瘤中的细胞间相互作用 影响不同亚群的分裂和存活率；我们还将确定表型 不同亚群之间的转变率，以捕获 SCLC 动态和可塑性。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 的发展和进展，并可能最终通过确定新的治疗方法 SCLC 亚群的关键相互作用。