Kinetic analysis of Myc-induced carcinogenesis in vivo

描述（由申请人提供）：Myc是一种高度多性的转录因子，协调细胞增殖的多个不同方面，其表达在人类癌症中经常被解除调控和/或升高。我们的研究表明，Myc不仅协调有序细胞扩增所需的各种细胞内程序-细胞代谢，细胞生长，细胞周期进程，去分化和凋亡-而且还协调一套细胞外程序，重组局部体细胞微环境并为细胞在其中间扩增做好准备。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Myc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。其次，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似乎是维持其引发的肿瘤所必需的。然而，在大多数肿瘤中，Myc本身并没有突变，相反，它似乎是近端致癌病变的内源性下游通道。内源性Myc活性在多大程度上是肿瘤维持所必需的？为什么？我们将从三个方面来解决这些问题。在目的1中，我们将使用我们完善的、动态定义的Myc诱导肿瘤发生的可逆切换胰腺β细胞小鼠模型，以确定Myc如何沉淀重组胰岛微环境的事件因果链。重点关注myc诱导的肿瘤血管生成，我们将确定炎症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及其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在多种组织中作用的后果，该模型允许Myc在任何靶组织中零星和可逆激活。利用这个模型，我们将特别关注Myc在肺部的致癌机制。在Aim 3中，我们将使用一种新的小鼠模型，在该模型中，我们可以在体内多种组织中可逆地抑制内源性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。

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.