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相关亚型的80% 死亡。铂耐药的迅速出现是导致这种死亡的主要原因。尽管最初 手术加化疗后，80%的患者肿瘤复发，并迅速产生化疗耐药。 尽管很少有基因突变与化疗耐药有关，但在很大一部分肿瘤中，驱动因素 化疗耐药的快速出现的原因尚不清楚。在这里，我们提出了非遗传机制在 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 将从全球转录重编程的角度解决铂耐药的出现。我们的 已发表的初步研究结果支持铂耐药产生于治疗诱导的假说。 种群水平的表观基因组和转录重编程。通过对表观基因组的整合分析 和多个对顺铂耐药的同基因细胞的转录本，我们鉴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)。第一个目标使用了尖端技术 基因组作图和操作技术，包括单细胞水平的CRISPR扰动，随后是 转录组分析，以确定哪些TF和TF-组合是将幼稚细胞重新编程为 抵抗状态。第二个目标是研究一种新的组合靶标，以实现合成杀伤力 HGSOC中的卡铂。这项提案的发现将为关键字的作用提供新的机械性见解 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.