ERG 在前列腺癌病理进展和靶向治疗敏感性调控过程中的分子机制

Genomic rearrangements leading to the overexpression of ETS family transcription factor ERG are amongst the most common molecular alteration in prostate cancer, occurring in approximately 50% of all cases. However，the molecular mechanisms underlying ERG-mediated oncogenesis in prostate cancer remain elusive. Our preliminary studies indicate that ERG promotes prostate pathological progression and confers resistance to combined PI3K/AR inhibition in PTEN loss context. These findings indicate the important interactions between AR, ERG and PTEN in prostate cancer where aberrations in these pathways are also significantly enriched. In this proposal, we are aiming to 1) determine the molecular mechanisms of ERG-mediated prostate cancer pathological progression, 2) decipher the mechanism of ERG regulated AR signaling pathway reprogram, and 3) elucidate the impact of ERG on response to PI3K/AR pathway inhibition. To achieve these Aims, we will leverage innovation approaches of new mouse and human prostate organoid technology, that enables precise mechanistic analysis of ERG function in ways not previously possible. Through these approaches we are optimally positioned to directly elucidate ERG-associated pathway which in turn lead to the identification of biomarkers to predict prostate cancer progression, and develop novel therapy targets.

ETS转录因子家族成员ERG的基因重排发生在约50%的前列腺癌病例中，是前列腺癌最常见的一种染色体重排。然而，ERG在前列腺癌起始过程中的作用机理，及其对雄激素阻断治疗的影响都非常不清楚。我们的前期研究表明，在PTEN缺失的条件下，ERG明显促进了前列腺癌的病理进展，并导致前列腺肿瘤细胞对雄激素和PI3K联合阻断治疗的拮抗。这一结果暗示，在前列腺肿瘤中显著富集的AR、ERG和PTEN基因改变之间密切相关，并可能参与肿瘤细胞的命运决定。本项目拟利用实验室建立的小鼠和人前列腺类器官培养技术，建立ERG相关的前列腺癌早期、中期、晚期和去势抵抗性肿瘤类器官模型体系，在整体水平上系统而全面的研究ERG基因重排在前列腺癌病理进展和AR/PI3K靶向治疗敏感性调控过程中的分子机制，揭示ERG相关信号通路与细胞命运决定的时空动态调控机制，并为进一步从前列腺癌病理机制中筛选新的治疗靶点和诊断标记物打下基础。