Successive responses to oncogenic aberrations in retinoblastoma genesis.

项目摘要 了解正常细胞如何转变为恶性肿瘤可能提供新的治疗和预防 机遇。然而，尽管许多促进癌症的基因变化已经被发现，而且 在模型设置中阐明了相应的信号通路，即介导致癌的细胞反应 在真正的人类癌细胞来源中的转化在很大程度上是未知的。这项研究旨在界定 调节儿童眼癌的细胞反应，视网膜母细胞瘤，这是好的 适合于这样的分析，因为起源细胞(成熟的锥体前体)是主要的启动突变 (双等位基因RB1失活)和惰性癌前阶段已经被发现，而且因为- Origin对启动致癌突变的增殖反应，通过癌前状态的进展，以及 视网膜母细胞瘤的出现可以在体外和体内实验中观察到并表现出其特征。这个 拟议的研究将探索持续的基因表达和细胞信号变化，这些变化是 锥体前体对RB1缺失的反应，包括调节细胞周期进入、增殖、撤退的变化 到惰性的癌前状态，或者失活以形成衰老样视网膜瘤，或者重新激活 形成高度增殖的视网膜母细胞瘤肿块。目标1将定义在以下方面发生的转录变化 对Rb丢失的反应，因为起源的锥体前体细胞在发育中走上了它的恶性轨迹 视网膜。目标2和3将集中在最近发现的早期基因表达反应及其对 锥体前体的增殖和横穿癌前阶段。AIM 2的核心是上调An 致癌的表观遗传调节因子，可使惰性的、癌前锥体前体和 视网膜母细胞瘤的出现。AIM 3的核心是下调PI3的负调控因子- 这可能促进Rb缺乏的视锥前体的存活和转化。目标4将 重点关注RB的结构、生化功能和抑制所需的下游机制 锥体前体细胞周期进入和穿越癌前阶段。我们会特别注意 不同Rb功能抑制视网膜母细胞瘤的不同阶段及其基因表达和细胞 调节RB效应的信号变化。总而言之，拟议的研究有望有所改善 理解人类原发癌细胞在其向 恶毒。反过来，改进的理解可能会揭示可以有针对性的漏洞，以便 预防遗传倾向儿童的视网膜母细胞瘤。

Project Summary Understanding how a normal cell becomes a malignant cancer may provide new therapeutic and prevention opportunities. However, although many genetic changes that promote cancer have been identified, and the corresponding signaling pathways elucidated in model settings, the cellular responses that mediate oncogenic transformation in an authentic human cancer cell-of-origin are largely unexplored. This study aims to define cellular responses that mediate the development of a childhood eye cancer, retinoblastoma, which is well suited to such analyses because the cell-of-origin (the maturing cone precursor), the major initiating mutation (biallelic RB1 inactivation), and an indolent pre-malignant stage have been identified, and because the cell-of- origin’s proliferative response to initiating oncogenic mutations, progression through a pre-malignant state, and emergence as a retinoblastoma tumor can be observed and characterized in in vitro and in vivo assays. The proposed studies will explore the successive gene expression and cell signaling changes that underlie the cone precursors’ responses to RB1 loss, including changes that mediate cell cycle entry, proliferation, retreat to an indolent pre-malignant state, and either deactivation to form a senescence-like retinoma or reactivation to form a highly proliferating retinoblastoma mass. Aim 1 will define the transcriptomic changes that occur in response to RB loss as the cone precursor cell of origin embarks on its malignant trajectory in the developing retina. Aims 2 and 3 will focus on recently identified early gene expression responses and their importance for cone precursor proliferation and traversal of the pre-malignant phase. Aim 2 centers on the up-regulation of an oncogenic epigenetic regulator, which may enable reactivation of indolent, pre-malignant cone precursors and emergence of retinoblastoma tumors. Aim 3 centers on the down-regulation of a negative regulator of PI3- kinase signaling, which may enhance the RB-deficient cone precursor survival and transformation. Aim 4 will focus on the RB structures, biochemical functions, and downstream mechanisms that are needed to suppress cone precursor cell cycle entry and traversal of the pre-malignant phase. Particular attention will be paid to the stages at which different RB functions contribute to suppress retinoblastoma and the gene expression and cell signaling changes that mediate RB effects. Together, the proposed studies are expected to improve understanding of the oncogenic responses of a human cancer cell-of-origin during its journey towards malignancy. In turn, the improved understanding may reveal vulnerabilities that can be targeted in order to prevent retinoblastoma in genetically predisposed children.