Transcriptional-translational conflict in bladder epithelial homeostasis and cancer

膀胱上皮稳态和癌症中的转录-翻译冲突

• 批准号: 10564590
• 负责人: Andrew Caleb Hsieh
• 金额: $ 58.81万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564590
• 关键词: ARID1A gene; Animal Model; Biology; Bladder; Cancer Patient; Cell Maintenance; Chromatin; Complex; Conflict (Psychology); Coupled; DNA Damage; Data; Disease; Elongation Factor; Epithelial Cells; Epithelial Physiology; Epithelium; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Goals; Homeostasis; Human; Impairment; In Vitro; Laboratories; Link; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mediating; Messenger RNA; Modality; Modeling; Molecular; Mus; Mutate; Mutation; Natural History; Nucleotides; Oncogenic; Organoids; PTEN gene; Pathogenesis; Patient-Focused Outcomes; Patients; Peptide Elongation Factor 2; Phenotype; Population; Process; Production; Proliferating; Protein Biosynthesis; Proteins; Regulation; Research; Specimen; System; TP53 gene; Therapeutic; Transcript; Translational Repression; Translations; Tumor Suppressor Proteins; Urothelial Cell; Urothelium; Work; cancer genome; carcinogenesis; cell transformation; chromatin protein; chromatin remodeling; clinical application; clinically significant; fitness; genome sequencing; improved; in vivo; in vivo Model; loss of function mutation; mRNA Translation; mouse model; novel; novel therapeutic intervention; parity; patient derived xenograft model; pharmacologic; polysome profiling; precision medicine; prevent; prognostic; programs; response; restoration; restraint; transcriptome; translational impact; tumor; tumor progression; tumorigenesis

ABSTRACT Chromatin remodeling and protein synthesis are tightly regulated processes that impact gene expression and cellular phenotypes. However, it is unknown to what extent these two regulatory mechanisms may be linked or independent in controlling normal epithelial physiology and disease states. We have uncovered a new functional relationship between the chromatin remodeler ARID1A and mRNA translation elongation. This link is involved in maintaining cellular fitness in the context of bladder carcinogenesis and represents a new tumor suppressive mechanism we call transcriptional-translational conflict. Loss of ARID1A triggers a simultaneous increase in oncogenic transcripts, but also inhibition of the translation elongation factor eEF2, which results in a reduction in protein synthesis and prevents cancer pathogenesis. However, this process can be reversed by restoring translation elongation, which enables the efficient synthesis of oncogenic mRNAs and cancer progression. This finding provides a unified gene expression model which explains why ARID1A is a context specific tumor suppressor. Importantly, ARID1A deficient tumors retain a sensitivity to pharmacologic inhibition of translation elongation initiation. Recently, our laboratory has developed and characterized new in vitro and in vivo models of both human and murine ARID1A deficient bladder cancer where we can also toggle translation elongation. We have used these models to discover a critical link between ARID1A and the process of mRNA translation elongation that is vital for urothelial homeostasis and bladder cancer progression. We hypothesize that transcriptional-translational conflict in urothelium lacking ARID1A is mediated through decreased eukaryotic elongation factor 2 (eEF2) activity, which when reversed unleashes a poised druggable oncogenic program sufficient to drive cancer progression. Our long-term objective is to utilize state-of-the-art mouse models and primary organoid systems, whole transcriptome polysome profiling, and patient derived xenografts to definitively investigate the fundamental link between ARID1A and protein synthesis regulation in a highly relevant population of bladder cancer patients. To do so, we will address the following aims: 1) Determine the relevance and mechanism of transcriptional-translational conflict in urothelial cell transformation and carcinogenesis; and 2) Elucidate how gene expression parity enables cancer progression and represents a context specific therapeutic vulnerability. This research will help us gain a deeper understanding of the biology of bladder cancer and open a new paradigm for treating patients with lethal disease. Our work is particularly important for the progress of precision medicine because it seeks to mechanistically tie a highly prevalent bladder cancer genotype (ARID1A loss) to a new treatment modality that holds therapeutic promise for bladder cancer patients.

抽象的 染色质重塑和蛋白质合成是受到严格调控的过程，影响基因表达和 细胞表型。然而，尚不清楚这两种监管机制在多大程度上存在联系或关联。 独立控制正常上皮生理和疾病状态。我们发现了一个新的功能 染色质重塑子 ARID1A 与 mRNA 翻译延伸之间的关系。此链接涉及 在膀胱癌发生的背景下维持细胞健康，代表了一种新的肿瘤抑制方法 我们称之为转录-翻译冲突的机制。 ARID1A 的丢失会触发同时增加 致癌转录物，而且还抑制翻译延伸因子 eEF2，从而导致 蛋白质合成并预防癌症发病机制。然而，这个过程可以通过恢复来逆转 翻译延伸，能够有效合成致癌 mRNA 并促进癌症进展。这 这一发现提供了一个统一的基因表达模型，解释了为什么 ARID1A 是一种背景特异性肿瘤 抑制器。重要的是，ARID1A 缺陷的肿瘤保留了对药物翻译抑制的敏感性 伸长起始。最近，我们的实验室开发并表征了新的体外和体内模型 人类和小鼠 ARID1A 缺陷型膀胱癌的研究，我们还可以切换翻译延伸。 我们使用这些模型发现了 ARID1A 和 mRNA 翻译过程之间的关键联系 伸长对于尿路上皮稳态和膀胱癌进展至关重要。我们假设 缺乏 ARID1A 的尿路上皮中的转录-翻译冲突是通过真核细胞减少介导的 延伸因子 2 (eEF2) 活性，当其被逆转时，会释放出一种蓄势待发的可药物致癌程序 足以推动癌症进展。我们的长期目标是利用最先进的小鼠模型和 原代类器官系统、全转录组多核糖体分析和患者来源的异种移植物以明确 在高度相关的人群中研究 ARID1A 和蛋白质合成调控之间的基本联系 膀胱癌患者。为此，我们将实现以下目标：1）确定相关性和 尿路上皮细胞转化和癌变中转录-翻译冲突的机制；和 2) 阐明基因表达奇偶性如何促进癌症进展并代表特定背景的治疗 脆弱性。这项研究将帮助我们更深入地了解膀胱癌的生物学并开放 治疗致命疾病患者的新范例。我们的工作对于进步特别重要 精准医学，因为它寻求机械地联系高度流行的膀胱癌基因型（ARID1A 损失）到一种新的治疗方式，为膀胱癌患者带来了治疗希望。