The Oncogene Activated Mitochondrial Unfolded Protein Response Regulates Senescence Biology

癌基因激活线粒体未折叠蛋白反应调节衰老生物学

• 批准号: 10598922
• 负责人: Julide T. Celebi
• 金额: $ 62.86万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-03 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598922
• 关键词: 3-Dimensional; Acetylation; Apoptosis; Benign; Biochemical; Biology; Cell Survival; Cells; Cellular Stress; Cellular biology; Clinic; Clinical; Cutaneous Melanoma; Data; Data Set; Development; Diagnosis; Disease; Distal; Dysplastic Nevus; Epigenetic Process; Eukaryota; Failure; Gene Expression; Genetic Transcription; Human; Immune; Immunocompetent; In Vitro; Laboratories; Lesion; Link; Literature; Lymphocyte; Malignant Neoplasms; Mediating; Metabolism; Mitochondria; Modeling; Molecular; Mus; Neoplasm Metastasis; Nevus; Nucleic Acid Regulatory Sequences; Oncogenes; Oncogenic; Organelles; Oxidative Phosphorylation; Pathway interactions; Patients; Phenotype; Positioning Attribute; Premalignant Cell; Process; Production; Prognostic Marker; Proteins; Quality Control; Risk; Sampling; Signal Pathway; Signal Transduction; Skin; Stress; System; Therapeutic; Tissues; cancer cell; cell type; cohort; cytokine; data integration; disease phenotype; experience; experimental study; gain of function; high risk; in vivo; in vivo Model; insight; interest; loss of function; malignant state; melanocyte; melanoma; mitochondrial metabolism; novel; permissiveness; premalignant; prevent; programs; promoter; recruit; repaired; response; senescence; skin lesion; success; transcriptome; transcriptome sequencing; tumor; tumor microenvironment; tumorigenesis

PROJECT SUMMARY Mitochondria created an evolutionary advantage for eukaryote and metazoan organization, and their impact on cell biology extends from anabolic and catabolic metabolism to determining the final moments of cell survival by engaging apoptosis. Throughout the last decade, interest in studying how mitochondria influence cancer cell biology led our laboratories to identify mechanisms linking oncogenic signaling (i.e., BRAFV600E / NRASG12V ) to multiple mitochondria-centric processes within malignant cells including altered mitochondrial dynamics, oxidative phosphorylation, and chemosensitivity. More recently, we focused on exploring how oncogenes intersect upon mitochondrial biology prior to transformation – which will likely provide molecular details into pre- malignant cell biology and early stages of disease. We commonly position our studies in the context of melanoma as we have extensive experience with primary human melanocytes, integrated cohorts of patient RNA-seq datasets and tissues, and multiple in vitro and in vivo models of early and late disease. For instance, the introduction of oncogenic signaling (BRAFV600E / NRASG12/Q60) in primary human melanocytes causes rapid oncogene-induced senescence (OIS), and this tumor-suppressive mechanism is reflected in patients who present with pre-malignant skin lesions in the clinic. Therefore, the scientific premise for this application is based on three novel observations: (i) primary human melanocytes expressing oncogenes rapidly expand their mitochondrial networks during OIS; (ii) this expansion is dictated by the undescribed activation of the ATF5- dependent mitochondrial unfolded protein response (mtUPR); and (iii) the mtUPR controls the rate and extent of OIS. While the mtUPR is a fundamental organelle-specific quality control signaling pathway that is essential to mitigate mitochondrial stress, no literature mechanistically connects oncogenic signaling to mtUPR activation, melanocyte biology, nor melanoma progression. In our preliminary experiments, we explored biochemical signaling, mitochondrial responses, cellular gain-of-function / loss-of-function approaches, and hundreds of patient samples to establish the hypothesis that the oncogene-activated ATF5-dependent mtUPR is a key signaling pathway that instructs melanocytes during OIS and its escape. In this R01 application, we propose three complimentary, but distinct, specific aims to examine this hypothesis using melanocytes, numerous models of early disease, and patient samples. Specific Aim #1: Interrogate the mechanistic relationship between oncogenic signaling, mtUPR, and OIS. Specific Aim #2: Identify the gene expression programs mediated and maintained by the mtUPR during OIS and early disease primary melanoma. Specific Aim #3: Define the impact of mtUPR activation in models of nevi and primary disease.

项目摘要 线粒体为真核生物和后生动物的组织创造了进化优势， 细胞生物学从合成代谢和分解代谢延伸到决定细胞存活的最后时刻， 参与细胞凋亡在过去的十年中，研究线粒体如何影响癌细胞的兴趣 生物学使我们的实验室鉴定了连接致癌信号的机制（即，BRAFV 600 E/NRASG 12 V）至 恶性细胞内的多个以线粒体为中心的过程，包括改变的线粒体动力学， 氧化磷酸化和化学敏感性。最近，我们专注于探索癌基因如何 在转化之前与线粒体生物学相交-这可能会为转化前提供分子细节， 恶性细胞生物学和疾病的早期阶段。我们通常将研究定位在黑色素瘤的背景下， 由于我们对原代人黑素细胞有丰富的经验，因此整合了患者RNA-seq 数据集和组织，以及早期和晚期疾病的多种体外和体内模型。你比如说 在原代人黑素细胞中引入致癌信号传导（BRAFV 600 E/NRASG 12/Q60）引起快速的 癌基因诱导的衰老（OIS），这种肿瘤抑制机制反映在 在临床上表现为癌前皮肤病变。因此，这一应用的科学前提是基于 关于三个新的观察结果：（i）表达癌基因的原代人类黑素细胞迅速扩张， OIS期间的线粒体网络;（ii）这种扩张是由未描述的ATF 5激活决定的， 依赖的线粒体未折叠蛋白反应（mtUPR）;和（iii）mtUPR控制的速率和程度， OIS。虽然mtUPR是一种基本的细胞器特异性质量控制信号通路， 减轻线粒体应激，没有文献将致癌信号传导与mtUPR活化机械地联系起来， 黑素细胞生物学，也不是黑色素瘤进展。在我们的初步实验中，我们探索了生物化学 信号传导，线粒体反应，细胞功能获得/功能丧失方法，以及数百种 患者样本，以建立假设，即癌基因激活的ATF 5依赖性mtUPR是一个关键， 在OIS期间指示黑素细胞及其逃逸的信号通路。在此R 01应用中，我们建议 三个互补的，但不同的，具体的目的是检验这一假设使用黑色素细胞，许多模型， 早期疾病和患者样本的信息。具体目标#1：探究以下机制之间的关系： 致癌信号、mtUPR和OIS。具体目标#2：确定介导的基因表达程序， 在OIS和早期疾病原发性黑色素瘤期间由mtUPR维持。具体目标#3：定义影响 在痣和原发性疾病模型中的mtUPR激活。