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Successive responses to oncogenic aberrations in retinoblastoma genesis.

对视网膜母细胞瘤发生中致癌畸变的连续反应。

基本信息

批准号：
10582627
负责人：
David Cobrinik
金额：
$ 32.24万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10582627
关键词：
Alleles Attention Behavior Biochemical Biological Assay Cell Cycle Cell Proliferation Cells Child Childhood Competence Complement Complex Cone DNA biosynthesis Development Down-Regulation EZH2 gene Early identification Epigenetic Process Gene Expression Generations Genes Genetic Predisposition to Disease Genomics Histones Human In Vitro Indolent Lesion Malignant - descriptor Malignant Neoplasms Mediating Methylation Modeling Molecular Monitor Mutation Normal Cell Oncogenic PIK3CG gene Phase Precancerous Conditions Predisposition Prevention Preventive Process Proliferating Proteins RB1 gene RNA Repression Retina Retinal Cone Retinoblastoma Retinoblastoma Protein Signal Pathway Signal Transduction Structure Testing Therapeutic Tissues Transactivation Tumor Suppressor Proteins Up-Regulation cancer cell cancer initiation cell transformation cell type epigenomics improved in vivo insight malignant neoplasm of eye malignant retina neoplasm novel novel therapeutic intervention novel therapeutics precursor cell premalignant prevent protein expression response senescence transcriptomics tumor tumorigenesis

项目摘要

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.

项目概要了解正常细胞如何变成恶性肿瘤可能提供新的治疗和预防机会。然而，尽管许多促进癌症的基因变化已被确定，并且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真正的人类癌细胞来源的转化很大程度上尚未被探索。本研究旨在定义介导儿童眼癌、视网膜母细胞瘤发展的细胞反应，这是一种很好的治疗方法适合此类分析，因为起源细胞（成熟锥体前体）是主要的起始突变（双等位基因 RB1 失活），并且已鉴定出惰性癌前阶段，并且因为细胞- 起源对起始致癌突变的增殖反应，通过癌前状态的进展，以及可以在体外和体内测定中观察和表征视网膜母细胞瘤的出现。这拟议的研究将探索连续的基因表达和细胞信号传导的变化视锥细胞前体对 RB1 丢失的反应，包括介导细胞周期进入、增殖、退缩的变化到惰性的恶变前状态，并且失活以形成衰老样视网膜瘤或重新激活以形成形成高度增殖的视网膜母细胞瘤肿块。目标 1 将定义发生在当原始视锥前体细胞在发育中开始走上恶性轨道时，对 RB 损失的反应视网膜。目标 2 和 3 将重点关注最近发现的早期基因表达反应及其对锥体前体增殖并穿越癌前阶段。目标 2 的重点是上调致癌表观遗传调节因子，可以重新激活惰性的、恶变前的锥体前体和视网膜母细胞瘤的出现。目标 3 集中于 PI3- 负调节因子的下调激酶信号传导，可能会增强 RB 缺陷锥体前体的存活和转化。目标4将重点关注抑制所需的RB结构、生化功能和下游机制锥体前体细胞周期进入并穿越癌前阶段。将特别关注不同 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介导 RB 效应的信号传导变化。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，加深的理解可能会揭示可针对的漏洞，以便预防有遗传倾向的儿童的视网膜母细胞瘤。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Reciprocal Induction of MDM2 and MYCN in Neural and Neuroendocrine Cancers.

MDM2 和 MYCN 在神经和神经内分泌癌中的相互诱导。

DOI：
10.3389/fonc.2020.563156
发表时间：
2020
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Tran HN;Singh HP;Guo W;Cambier L;Riggan L;Shackleford GM;Thornton ME;Grubbs BH;Erdreich-Epstein A;Qi DL;Cobrinik D
通讯作者：
Cobrinik D

Episodic live imaging of cone photoreceptor maturation in GNAT2-EGFP retinal organoids.

DOI：
10.1242/dmm.050193
发表时间：
2023-11-01
期刊：
Disease models & mechanisms
影响因子：
4.3
作者：
通讯作者：

Retinoblastoma.

DOI：
10.1038/nrdp.2015.21
发表时间：
2015-08-27
期刊：
Nature reviews. Disease primers
影响因子：
0
作者：
Dimaras H;Corson TW;Cobrinik D;White A;Zhao J;Munier FL;Abramson DH;Shields CL;Chantada GL;Njuguna F;Gallie BL
通讯作者：
Gallie BL

Rb suppresses human cone-precursor-derived retinoblastoma tumours.

DOI：
10.1038/nature13813
发表时间：
2014-10-16
期刊：
NATURE
影响因子：
64.8
作者：
Xu, Xiaoliang L.;Singh, Hardeep P.;Wang, Lu;Qi, Dong-Lai;Poulos, Bradford K.;Abramson, David H.;Jhanwar, Suresh C.;Cobrinik, David
通讯作者：
Cobrinik, David