Kinetic analysis of Myc-induced carcinogenesis in vivo

摘要 MYC是一种高度多效性的转录因子，协调细胞增殖的多个不同方面，并 其在人类癌症中的表达经常被解除和/或上调。我们的研究表明，Myc 不仅编排了有序细胞扩张所需的各种细胞内程序-细胞 新陈代谢、细胞生长、细胞周期进程、去分化和凋亡--但也有一套 重组局部体细胞微环境并为细胞扩张做准备的细胞外程序 在它的中间。Myc的致癌激活劫持了所有这些不同的过程，使致癌Myc能够 指导和维护肿瘤表型的多个方面。在这项提案中，我们将解决三个问题 Myc肿瘤生物学中的关键问题。首先，体内体细胞中Myc的激活如何指导和 在直接的躯体微环境中保持广泛的致癌变化。第二，Myc好吗？ 由激活Myc的细胞/组织类型决定的致癌作用？第三，致癌活性 MYC似乎对维持其引起的肿瘤是必要的。然而，Myc本身并没有在大多数情况下发生突变 相反，肿瘤似乎是近端致癌病变的内源性下游管道。至 维持肿瘤需要多大程度的内源性Myc活性？为什么？我们将解决这些问题 三个目标中的问题。 在目标1中，我们将使用我们成熟的和动态定义的可逆切换的胰岛β细胞。 Myc诱导肿瘤发生的小鼠模型，以确定Myc如何促成 重组胰岛微环境。专注于Myc诱导的肿瘤血管生成，我们将 确定炎性细胞因子和浸润性细胞在启动和维持肿瘤血管中的作用 以及这在肿瘤维持中所起的作用。在目标2中，我们将讨论#年Myc行动的后果 使用一种新的转基因小鼠模型，允许Myc在体内的零星和可逆激活 任何目标组织。利用这一模型，我们将重点研究Myc在肺中的致癌机制。在AIM 3中 我们将使用一种新的小鼠模型，在该模型中，我们可以可逆地抑制内源性Myc功能 在活体组织中确定内源性Myc在维持正常和肿瘤中的作用 纸巾。

Abstract 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.