Kinetic analysis of Myc-induced carcinogenesis in vivo

Myc 诱导体内致癌作用的动力学分析

• 批准号: 7760940
• 负责人: GERARD IAN EVAN
• 金额: $ 34.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760940
• 关键词: Address; Apoptosis; Cell Cycle Progression; Cell Proliferation; Cells; Event; Histocompatibility Testing; Human; Inflammatory; Kinetics; Lesion; Lung; Maintenance; Malignant Neoplasms; Metabolism; Mitotic Cell Cycle; Modeling; Mutate; Names; Oncogenic; Pathway interactions; Phenotype; Play; Principal Investigator; Process; Research; Role; Somatic Cell; Structure of beta Cell of islet; Tissues; Transgenic Mice; Tumor Angiogenesis; Tumor Biology; carcinogenesis; cell growth; cytokine; extracellular; in vivo; islet; mouse model; neoplastic; novel; programs; therapeutic target; transcription factor; tumor; tumorigenesis; tumorigenic

DESCRIPTION (provided by applicant): Myc is a highly pleiotropic transcription factor that coordinates multiple, diverse aspects of cell proliferation and whose expression is frequently deregulated and/or elevated in human cancers. Our studies indicate that Myc orchestrates not only the wide variety of intracellular programs necessary for orderly cell expansion - cell metabolism, cell growth, cell cycle progression, de-differentiation and apoptosis - but also a suite of extracellular programs that reorganize the local somatic microenvironment and prepare it for the cell expanding in its midst. Oncogenic activation of Myc hijacks all of these diverse processes, allowing oncogenic Myc to instruct and maintain multiple aspects of the neoplastic phenotype. In this proposal, we will address three pivotal questions in Myc tumor biology. First, how does Myc activation in somatic cells in vivo instruct and maintain widespread tumorigenic changes in the immediate somatic microenvironment. Second, how is Myc oncogenic action determined by the cell/tissue type in which Myc is activated? Third, oncogenically activated Myc appears necessary for maintenance of tumors that it elicits. However, Myc is not itself mutated in most tumors but, instead, appears to act as an endogenous downstream conduit of proximal oncogenic lesions. To what extent is endogenous Myc activity required for tumor maintenance, and why? We will address these questions in three aims. In Aim 1 we will use our well-established and kinetically defined reversibly switchable pancreatic beta cell mouse model of Myc-induced tumorigenesis to ascertain how Myc precipitates the causal chain of events that reorganize the islet microenvironment. Focusing specifically on Myc-induced tumor angiogenesis, we will ascertain the role of inflammatory cytokines and infiltrating cells in initiating and maintaining tumor vasculature and the role this plays in tumor maintenance. In Aim 2 we will address the consequences of Myc action in multiple tissues using a novel transgenic mouse model that allows sporadic and reversible activation of Myc in any target tissue. Using this model, we will specifically focus on Myc oncogenic mechanism in lung. In Aim 3 we will use a novel mouse model in which we can reversibly inhibit endogenous Myc function in multiple tissues in vivo to determine the role played by endogenous Myc in maintenance of normal and neoplastic tissues. Relevance Myc is a pivotal regulator of cell growth that is aberrantly activated in many human cancers. Because it integrates so many diverse pathways necessary for tumorigenesis, it and its direct downstream agents are in principle attractive candidates for therapeutic targeting of many cancers. In this proposal we delineate how Myc exerts its multifarious tumorigenic effects in differing tissues and ascertain the extent to which Myc function is required to drive formation of cancers and, thereafter, maintain them.

描述（由申请人提供）：Myc是一种高度多效性的转录因子，其协调细胞增殖的多个不同方面，并且其表达在人类癌症中经常失调和/或升高。我们的研究表明，Myc不仅协调了细胞有序扩增所需的各种细胞内程序-细胞代谢，细胞生长，细胞周期进展，去分化和凋亡-而且还协调了一套细胞外程序，这些程序重组了局部体细胞微环境，并为其中间的细胞扩增做好准备。Myc的致癌激活劫持了所有这些不同的过程，允许致癌Myc指导和维持肿瘤表型的多个方面。在本提案中，我们将解决Myc肿瘤生物学中的三个关键问题。首先，体内体细胞中Myc的激活如何指导和维持直接体细胞微环境中广泛的致瘤性变化。第二，Myc的致癌作用是如何由Myc被激活的细胞/组织类型决定的？第三，致癌激活的Myc似乎是维持其所诱发的肿瘤所必需的。然而，Myc本身在大多数肿瘤中并不突变，而是似乎作为近端致癌病变的内源性下游管道。肿瘤维持需要内源性Myc活性到什么程度，为什么？我们将从三个方面来探讨这些问题。在目标1中，我们将使用我们完善的和动力学定义的Myc诱导的肿瘤发生的可逆可转换胰腺β细胞小鼠模型来确定Myc如何沉淀重组胰岛微环境的事件的因果链。特别关注Myc诱导的肿瘤血管生成，我们将确定炎性细胞因子和浸润细胞在启动和维持肿瘤血管系统中的作用，以及这在肿瘤维持中的作用。在目标2中，我们将使用一种新的转基因小鼠模型来解决Myc作用在多个组织中的后果，该模型允许Myc在任何靶组织中的零星和可逆激活。使用该模型，我们将特别关注Myc在肺中的致癌机制。在目标3中，我们将使用一种新的小鼠模型，其中我们可以在体内可逆地抑制多种组织中的内源性Myc功能，以确定内源性Myc在维持正常和肿瘤组织中所起的作用。 相关性Myc是细胞生长的关键调节因子，在许多人类癌症中被异常激活。因为它整合了肿瘤发生所必需的如此多的不同途径，所以它及其直接下游试剂原则上是许多癌症的治疗靶向的有吸引力的候选者。在这个提议中，我们描述了Myc如何在不同组织中发挥其多种致瘤作用，并确定Myc功能在多大程度上需要驱动癌症的形成，然后维持它们。