Chemo-mediated transcriptional reprogramming in ovarian cancer

卵巢癌中化疗介导的转录重编程

• 批准号: 10709477
• 负责人: Mazhar Adli
• 金额: $ 45.24万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709477
• 关键词: ATAC-seq; Acute; Architecture; Biology; Carboplatin; Carcinoma; Cell Reprogramming; Cells; Cessation of life; Chemoresistance; Chromatin; Cisplatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DNA Damage; DNA Repair; DNA Sequence Alteration; Data; Dose; Enhancers; Epigenetic Process; Gatekeeping; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; Growth; Immunocompetent; In Vitro; Malignant - descriptor; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Maps; Measures; Mediating; Modeling; Molecular; Non-Malignant; Operative Surgical Procedures; Ovarian Serous Adenocarcinoma; Pathway interactions; Patients; Platinum; Play; Population; Primary Neoplasm; Prognosis; Publishing; Recurrence; Relapse; Repression; Research; Resistance; Role; Sampling; Serous; Technology; Testing; Therapeutic; Tumor Debulking; Tumor Immunity; Tumor Tissue; Up-Regulation; Work; arginine methyltransferase; cancer cell; cancer subtypes; cancer therapy; chemotherapy; clinically relevant; cohort; combinatorial; comparative; epigenome; epigenomics; genome editing; genome-wide; improved; in vivo; insight; mortality; non-genetic; novel; novel therapeutic intervention; programmed cell death ligand 1; programs; response; screening; single-cell RNA sequencing; stem-like cell; therapeutic target; therapeutically effective; tool; transcription factor; transcriptional reprogramming; transcriptome; transcriptomic profiling; transcriptomics; tumor

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.

抽象的 高级浆液性癌（HGSC）是最具侵略性的OC亚型，占OC相关的80％ 死亡人数。铂（PT）抗性的快速出现是这种死亡率的主要原因。尽管最初 在80％的患者中，对手术加化学疗法，肿瘤缓解和迅速变化的反应。 尽管很少有遗传突变与化学抗性有关，但在很大一部分肿瘤中，驱动因素 化学抗性的快速出现尚不清楚。在这里，我们建议非遗传机制发挥作用 在控制高级浆液卵巢癌中细胞过渡到抗性状态的重要组成部分。我们 将从全球转录重编程的角度解决PT抗性的出现。我们的 已发表的初步发现支持了以下假设，即PT抗药性来自治疗诱导的 人群级的表观基因组和转录重编程。通过表观基因组学的综合分析 以及多个天真和顺铂的同源性细胞的转录组，我们确定了抗性态特异性 超级增强剂及其目标转录因子网络（TFN）。第一个目标员工尖端 基因组映射和操纵技术，包括单细胞级CRISPR扰动，然后是 转录组分析以确定哪些TF和TF组合对于将幼稚的细胞重新编程为 抵抗状态。第二个目标调查了一个新颖的组合靶标，以实现合成的致死性 HGSOC中的卡铂。该提案的发现将提供有关关键作用的新机械洞察力 转录因子网络，该网络控制卵巢癌的铂耐药性。