Successive responses to oncogenic aberrations in retinoblastoma genesis.

项目摘要 了解正常细胞如何变成恶性癌症可能会提供新的治疗和预防方法 机会然而，尽管已经确定了许多促进癌症的遗传变化， 在模型设置中阐明了相应的信号通路，介导致癌的细胞反应， 在真实的人癌细胞起源中的转化在很大程度上是未探索的。本研究旨在定义 细胞反应介导的儿童眼癌，视网膜母细胞瘤，这是很好的发展， 适合这样的分析，因为细胞的起源（成熟锥前体），主要的起始突变， （双等位基因RB 1失活），和惰性癌前阶段已经确定，因为细胞的- 起源对起始致癌突变的增殖反应，通过癌前状态的进展，和 作为成视网膜细胞瘤肿瘤的出现可以在体外和体内测定中观察和表征。的 拟议的研究将探索连续的基因表达和细胞信号转导的变化，这些变化是细胞凋亡的基础。 视锥前体对RB 1缺失的反应，包括介导细胞周期进入、增殖、消退的变化， 到惰性癌前状态，或者失活形成衰老样视网膜瘤，或者再活化形成衰老样视网膜瘤。 形成高度增殖的视网膜母细胞瘤块。目的1将定义转录组的变化，发生在 作为起源的视锥前体细胞在发育过程中开始其恶性轨迹， 视网膜。目的2和3将集中在最近确定的早期基因表达反应及其重要性， 视锥细胞前体增殖和癌前阶段的穿越。目标2的中心是上调一个 致癌表观遗传调节因子，其可以使惰性的、癌前锥前体的再活化， 视网膜母细胞瘤的出现。目标3集中在PI 3 - 1负调节子的下调上。 激酶信号传导，这可能会增强RB缺陷锥前体的生存和转化。目标4将 重点是RB结构，生化功能和下游机制，需要抑制 视锥前体细胞周期进入和恶性前阶段的穿越。将特别注意 不同RB功能有助于抑制视网膜母细胞瘤以及基因表达和细胞的阶段 调节RB效应的信号变化。总之，拟议的研究预计将改善 了解人类癌细胞起源过程中的致癌反应， 恶性肿瘤反过来，更好的理解可能会揭示可以针对的漏洞，以便 预防遗传易感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.