Defining the Role of ERG in Modulating the AR Cistrome and Antiandrogen Sensitivity

 描述（由申请人提供）：ETS家族转录因子（ERG、ETV 1、ETV 4、ETV 5、FLI 1）通过基因组融合的过表达是前列腺癌中最常见的分子畸变，发生在所有病例的一半中。将ERG置于雄激素调节的TMRPSS 2基因下的TMPRSS 2-ERG融合是主要的融合，在80- 90%的所有ETS阳性癌症中发现。前列腺癌中ETS介导的肿瘤发生的分子机制仍然难以捉摸。在基因工程小鼠模型（GEMM）中，单独的ERG表达不足以驱动前列腺肿瘤发生。然而，它会导致雄激素受体基因组结合谱（AR顺式组）的急剧重编程。与Pten损失结合，ERG促进肿瘤发生以及显著的转录组变化，并赋予对组合的PI 3 K/AR通路抑制的抗性，这是一种在单独Pten损失引发的前列腺肿瘤中高度有效的疗法。这些发现强调了AR，ERG和PTEN之间相互作用的重要生物学基础，不仅在小鼠和人类前列腺癌模型中，而且在人类前列腺癌临床标本中，这些途径中的畸变也高度相关。这个R 01项目将通过以下方式研究这些相互作用的分子细节：（i）确定ERG重新编程AR顺式体的机制，创造一种前列腺被启动以响应上游信号的状态（例如，Pten损失），（ii）阐明Pten损失下游的信号传导事件，其激活小鼠和人前列腺组织中ERG介导的转录模块，和（iii）确定ERG对AR途径抑制反应的影响。为了实现这些目标，我们将广泛使用新的小鼠和人类前列腺类器官技术，该技术由我们的团队产生，能够以以前不可能的方式对定义的管腔和基底前列腺上皮细胞群体进行精确的机械分析。我们将 利用计算系统生物学中的创新方法（Andrea Califano，哥伦比亚）来预测与ERG合作的Pten丢失所调节的候选信号通路和转录因子。

 DESCRIPTION (provided by applicant): Overexpression of ETS family transcription factors (ERG, ETV1, ETV4, ETV5, FLI1) through genomic fusion is the most common molecular aberration in prostate cancer, occurring in half of all cases. The TMPRSS2-ERG fusion that places ERG under the androgen-regulated TMRPSS2 gene is the predominant fusion, found in 80- 90% of all ETS-positive cancers. The molecular mechanisms underlying ETS-mediated oncogenesis in prostate cancer remain elusive. In genetically engineered mouse models (GEMM), ERG expression alone is not sufficient to drive prostate tumorigenesis. However, it causes dramatic reprogramming of the androgen receptor genomic binding profile (AR cistrome). In conjunction with Pten loss, ERG promotes tumorigenesis as well as significant transcriptome changes and confers resistance to combined PI3K/AR pathway inhibition, a therapy that is highly effective in prostate tumors initiated by Pten loss alone. These findings underscore the important biology that underlies interactions between AR, ERG and PTEN not only in mouse and human prostate cancer models, but also in human prostate cancer clinical specimens where aberrations in these pathways are also highly linked. This R01 project will examine the molecular details underlying these interactions by: (i) determining the mechanisms by which ERG reprograms the AR cistrome, creating a state where the prostate is primed to respond to upstream signals (e.g., Pten loss), (ii) elucidating the signaling events downstream of Pten loss that activate ERG-mediated transcription modules in mouse and human prostate tissue and (iii) determining the impact of ERG on response to AR pathway inhibition. To achieve these Aims, we will make extensive use of new mouse and human prostate organoid technology, generated by our group that enables precise mechanistic analysis of defined populations of luminal and basal prostate epithelial cells in ways not previously possible. We will leverage innovation approached in computational systems biology (Andrea Califano, Columbia) to predict candidate signaling pathways and transcription factors modulated by Pten loss that cooperate with ERG.