Cellular Predisposition to Retinoblastoma Tumorigenesis

描述（由申请人提供）：癌症可能是由于使特定细胞类型对特定致癌突变敏感的信号蛋白的“正常”表达引起的。然而，细胞类型特异性信号通路易患特定癌症的方式知之甚少。视网膜母细胞瘤是解决这个问题的合适模型，因为视网膜母细胞瘤起源细胞特别倾向于在RB 1基因失活的情况下启动肿瘤发生。因此，本项目旨在识别和表征使视网膜母细胞瘤细胞对Rb功能丧失敏感的特定信号。 初步研究确定了视锥光感受器前体细胞（CP）作为候选视网膜母细胞瘤细胞的起源，并表明，人类CP是独特的视网膜细胞中，他们显着表达MDM 2癌蛋白和甲状腺激素受体亚型，TR？2，这也是突出的前体Rb-缺陷小鼠垂体瘤。他们还透露，MDM 2和TR？2是必不可少的视网膜母细胞瘤细胞的增殖和生存，MDM 2是需要抑制致癌应激反应，TR？2是维持另一种蛋白质的表达所必需的Rb缺陷型肿瘤的发展，F盒蛋白Skp 2。为了确定这些CP功能是否是视网膜母细胞瘤肿瘤发生的基础，目标1将确定锥细胞回路在原发性人类CP对Rb耗竭的反应中的作用。目的2将通过检查Rb缺陷小鼠CP中的异位MDM 2表达（来自视锥靶向转基因或来自完整的人MDM 2基因座）是否在体内使CP增殖失调并导致CP衍生的视网膜母细胞瘤来扩展这些体外研究。目标3旨在确定TR的作用？2在视网膜母细胞瘤细胞增殖和存活中的作用，并将具体评价TR？2是促进Skp 2表达所必需的，并通过拮抗相关的TR？1个同种型。目标4将评估TR是否？2有助于Rb缺乏小鼠垂体瘤在体内的发展，类似于其对人视网膜母细胞瘤细胞在体外的影响，并将定义TR的细胞效应？2引起这些肿瘤的异常增殖的Rb缺陷细胞的损失。 总之，这些研究将评估是否“正常”CP电路敏感锥前体的致癌作用RB 1失活。这些研究可能会产生超出视网膜母细胞瘤的影响，通过定义通常与Rb丢失合作的细胞类型特异性特征，使Rb缺陷型癌症的发展成为可能。

DESCRIPTION (provided by applicant): Cancers may arise due to the "normal" expression of signaling proteins that sensitize specific cell types to specific oncogenic mutations. However, the means by which cell type-specific signaling pathways predispose to particular cancers is poorly understood. Retinoblastoma is a suitable model with which to address this issue, as the retinoblastoma cell of origin is exceptionally predisposed to initiate tumorigenesis in the event that the RB1 gene is inactive. Accordingly, this project aims to identify and characterize specific signals that sensitize the retinoblastoma cell of origin to the loss of Rb function. Preliminary Studies identified cone photoreceptor precursors (CPs) as a candidate retinoblastoma cell of origin and showed that human CPs are unique among retinal cells in that they prominently express the MDM2 oncoprotein and a thyroid hormone receptor isoform, TR?2, that is also prominent in the precursors to Rb- deficient mouse pituitary tumors. They also revealed that MDM2 and TR?2 are essential for retinoblastoma cell proliferation and survival, that MDM2 is needed to suppress the oncogenic stress response, and that TR?2 is needed to sustain the expression of yet another protein that is essential to the development of Rb-deficient tumors, the F-box protein Skp2. To determine whether these CP features underlie retinoblastoma tumorigenesis, Aim 1 will define the roles of the cone circuitry in the response of primary human CPs to Rb depletion. Aim 2 will extend these in vitro studies by examining whether ectopic MDM2 expression in Rb- deficient mouse CPs - either from a cone-targeted transgene or from an intact human MDM2 locus - deregulates CP proliferation and elicits CP-derived retinoblastomas in vivo. Aim 3 seeks to define the role of TR?2 in retinoblastoma cell proliferation and survival, and will specifically evaluate whether TR?2 is needed to promote Skp2 expression and acts by antagonizing the related TR?1 isoform. Aim 4 will evaluate whether TR?2 contributes to the development of Rb-deficient mouse pituitary tumors in vivo, similar to its effects on human retinoblastoma cells in vitro, and will define the cellular effects of TR?2 loss in the abnormally proliferating Rb-deficient cells that give rise to these tumors. Together, these studies will evaluate whether "normal" CP circuitry sensitizes cone precursors to the oncogenic effects of RB1 inactivation. The studies are likely to have an impact extending beyond retinoblastoma, by defining cell type-specific features that commonly collaborate with Rb loss to enable the development of Rb-deficient cancers.