ELUCIDATING MECHANISMS OF CELL COMPETITION DURING DEVELOPMENT

阐明发育过程中细胞竞争的机制

• 批准号: 10476372
• 负责人: Erika A Bach
• 金额: $ 37.84万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10476372
• 关键词: Animals; Antioxidants; Apoptosis; Apoptotic; Binding Proteins; Biological Assay; Biological Process; Brain; Cancer Etiology; Cell Survival; Cells; Cessation of life; Data; Development; Disadvantaged; Disease; Drosophila genus; Enzymes; Event; Evolution; G-Protein-Coupled Receptors; Gene Expression; Genes; Genetic; Genetic Heterogeneity; Genetic Screening; Goals; Growth; Human; Insulin Receptor; Knowledge; Lesion; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Neoplasm Metastasis; Oncogenes; Oncogenic; Oranges; Organism; Orphan; Oxidases; Pathway interactions; Population; Premalignant Cell; Proteins; Proto-Oncogenes; Publications; Publishing; Quality Control; Reactive Oxygen Species; Regenerative response; Relaxin; Reporting; Role; Signal Transduction; Stress; Testing; Text; Tissues; Up-Regulation; Wing; Work; base; cancer therapy; cell type; design; extracellular; fitness; human disease; imaginal disc; insight; insulin-like peptide; neoplastic; neuroglian; next generation sequencing; novel therapeutics; receptor; response; success; transcription factor; transcriptomics; tumor; tumor growth; tumor progression

Project Summary The goal of this proposal is to understand how cell competition regulates tissue growth during development and how such mechanisms can be subverted during diseases like cancer. Our lab and other labs have shown that genetic heterogeneity between neighboring populations provokes competitive interactions between them, resulting in the selective elimination of the weaker population (the losers) and the expansion of the stronger one (the winners). During classical cell competition wild-type cells eliminate viable but sub-optimal cells. This type of cell competition functions as a quality control mechanism to selectively remove suboptimal cells from a tissue. During super-competition, cells with higher levels of oncogenes like STAT and Myc kill their wild-type neighbors. Super-competition functions during cancer progression and metastasis. While competitive interactions are conserved and are increasingly well documented, the mechanisms regulating the elimination of the weaker cells or the expansion of the stronger cells are poorly understood. Through next-generation sequencing, we identified two soluble stress-responsive factors that are produced by STAT winners and that promote their competitive fitness. Here, we will test the roles of these factors in cell competition. Aim 1 is focused on the role of the damage-response pathway in disadvantaging losers or increasing winner fitness in super- competition. Aim 2 will test the role of extracellular reactive oxygen species in killing losers and/or boosting winner function in both classical cell competition and super-competition. We envision that our studies will elucidate molecular and cellular events employed by pre-cancerous cells to establish themselves within a tissue and that might be operative when these cells progress into fully neoplastic lesions.

项目摘要 该提案的目的是了解细胞竞争如何调节组织生长 在癌症等疾病期间，发展以及如何颠覆这种机制。我们的实验室和其他实验室 已经表明，邻近种群之间的遗传异质性会激发竞争性相互作用 在他们之间，导致选择性消除较弱的人口（失败者）和扩张 强者（获胜者）。在经典细胞竞争期间，野生型细胞消除了可行但优化 细胞。这种类型的细胞竞争是一种质量控制机制，可有选择地删除次优 来自组织的细胞。在超级竞争期间，具有较高水平的癌基因的细胞（如STAT和MYC）杀死了它们 野生型邻居。癌症进展和转移过程中的超竞争功能。虽然有竞争力 相互作用是保守的，并且越来越有记录，调节消除的机制 较弱的细胞或较强细胞的扩展知之甚少。通过下一代 测序，我们确定了由Stat Winners产生的两个可溶性应力响应因素，并且 促进他们的竞争健身。在这里，我们将测试这些因素在细胞竞争中的作用。 AIM 1专注于 关于损害响应途径在不利的失败者或增加超级赢家健康方面的作用 竞赛。 AIM 2将测试细胞外活性氧在杀死失败者和/或提升的作用 在古典细胞竞争和超级竞争中的获胜者功能。我们设想我们的学习将 阐明癌细胞在组织中建立自己的分子和细胞事件 当这些细胞发展为完全肿瘤病变时，这可能是可操作的。