Chemo-mediated transcriptional reprogramming in ovarian cancer

摘要 高级别浆液性癌（HGSC）是最具侵袭性的OC亚型，占OC相关肿瘤的80%。 死亡铂（Pt）耐药性的迅速出现是这种死亡率的主要原因。尽管最初 在对手术加化疗有反应的患者中，肿瘤复发并在80%的患者中迅速变得耐药。 尽管很少有基因突变与化疗耐药性相关，但在大部分肿瘤中， 耐药性的迅速出现是未知的。在这里，我们提出，非遗传机制发挥作用， 在高级别浆液性卵巢癌中调节细胞向耐药状态转变的重要部分。我们 将从全局转录重编程的角度解决Pt抗性的出现。我们 已发表的和初步的研究结果支持这一假设，即铂耐药出现治疗诱导的 群体水平的表观基因组和转录重编程。通过对表观基因组的综合分析 和转录组的多个幼稚和顺铂耐药的同基因细胞，我们确定了耐药状态特异性 超级增强子及其靶向转录因子网络（TFN）。第一个目标是利用尖端技术 基因组作图和操作技术，包括单细胞水平的CRISPR扰动， 转录组分析，以确定哪些TF和TF组合是将幼稚细胞重编程为 抵抗状态。第二个目标是研究一种新的组合靶点，以实现合成杀伤力， 卡铂治疗HGSOC。这项提案的发现将为关键的作用提供新的机制见解。 调控卵巢癌铂耐药的转录因子网络。

Abstract High-grade serous carcinoma (HGSC) is the most aggressive OC subtype that accounts for 80% of OC-related deaths. Rapid emergence of platinum (Pt)-resistance is the main reason for this mortality. Despite initial response to surgery plus chemotherapy, tumors relapse and rapidly become chemoresistant in 80% of patients. Although few genetic mutations have been associated with chemoresistance, in a large fraction of tumors, drivers of the chemoresistance's rapid emergence are unknown. Here we propose that non-genetic mechanisms play an important part in regulating cellular transition to a resistant state in high grade serous ovarian cancer. We will tackle the emergence of Pt resistance from a global transcriptional reprogramming point of view. Our published and preliminary findings support the hypothesis that Pt resistance emerges from therapy-induced population-level epigenomic and transcriptional reprogramming. Through integrative analysis of epigenomes and transcriptomes of multiple naïve and cisplatin-resistant isogenic cells, we identified resistant-state specific super-enhancers and their target transcription factor networks (TFN). The first aim employs cutting edge genomic mapping and manipulation technologies including single cell-level CRISPR-perturbations followed by transcriptome profiling to identify which TFs and TF-combinations are necessary to reprogram naïve cells into the resistant state. The second aim investigates a novel combinatorial target to achieve synthetic lethality with carboplatin in HGSOC. The findings from this proposal will provide new mechanistic insight into the role of key transcription factor network that govern platinum resistance in ovarian cancer.