Kinetic analysis of Myc-induced carcinogenesis in vivo

描述(申请人提供)：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，其表达在人类癌症中经常被解除调控和/或上调。我们的研究表明，Myc不仅协调细胞有序扩张所需的各种细胞内程序--细胞新陈代谢、细胞生长、细胞周期进展、去分化和凋亡--而且还协调一套细胞外程序，重组局部躯体微环境，为细胞在其中间扩张做好准备。Myc的致癌激活阻断了所有这些不同的过程，允许致癌的Myc指示和维持肿瘤表型的多个方面。在这项提案中，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的激活如何在直接的体细胞微环境中指导和维持广泛的致癌变化。第二，Myc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似乎对维持其引起的肿瘤是必要的。然而，在大多数肿瘤中，Myc本身并没有发生突变，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维持肿瘤所必需的，为什么？我们将通过三个目标来解决这些问题。在目标1中，我们将使用我们成熟的、动态定义的可逆切换的胰岛β细胞小鼠模型来确定Myc如何加速重组胰岛微环境的因果链。重点是Myc诱导的肿瘤血管生成，我们将确定炎症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，我们将使用一种新的转基因小鼠模型来解决Myc在多个组织中作用的后果，该模型允许在任何目标组织中零星和可逆地激活Myc。利用这一模型，我们将重点研究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，在该模型中，我们可以在体内多个组织中可逆地抑制内源性Myc的功能，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。由于它整合了肿瘤发生所必需的许多不同的途径，它及其直接的下游药物原则上是许多癌症靶向治疗的有吸引力的候选药物。在这项建议中，我们描述了Myc如何在不同的组织中发挥其不同的致癌作用，并确定Myc功能在多大程度上需要驱动癌症的形成，并在此后维持它们。

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.