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

基本信息

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
项目类别：
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

项目摘要

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组织创造了进化优势，它们对细胞生物学从合成代谢和分解代谢代谢延伸，以确定细胞存活的最后时刻引人入胜的凋亡。在过去的十年中，对线粒体如何影响癌细胞的兴趣生物学导致我们的实验室确定连接致癌信号传导（即BRAFV600E / NRASG12V）的机制恶性细胞内的多个以线粒体为中心的过程，包括改变线粒体动力学，氧化磷酸化和化学敏感性。最近，我们专注于探索如何致癌在转化之前就线粒体生物学相交 - 这可能会提供分子细节恶性细胞生物学和疾病的早期阶段。我们通常在黑色素瘤的背景下将研究定位由于我们在原发性人类黑色素细胞方数据集和组织，以及早期和晚期疾病的多个体外和体内模型。例如，在原代黑素细胞中引入致癌信号传导（BRAFV600E / NRASG12 / Q60）会导致迅速癌基因诱导的感应（OIS），并且这种肿瘤抑制机制反映在患者中诊所中有恶性的皮肤病变。因此，此应用程序的科学前提是基于在三个新颖的观察结果中：（i）表达癌基因的原代人黑色素细胞迅速扩展 OIS期间的线粒体网络；（ii）这种扩展是由ATF5-未描述的激活决定的依赖性线粒体展开的蛋白质反应（MTUPR）；（iii）MTUPR控制 OIS。 MTUPR是一种基本的有机特异性质量控制信号传导途径，这对于减轻线粒体应力，没有文献将致癌信号传导与MTUPR激活联系起来，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，我们探索了生化信号传导，线粒体反应，蜂窝功能获得 /功能丧失方法以及数百种患者样本确定癌基因激活ATF5依赖性mtupr的假设是关键信号通路指示OIS期间的黑素细胞及其逃生。在此R01应用程序中，我们建议三个免费但独特的特定目的是使用黑色素细胞检查这一假设，众多模型早期疾病和患者样本。特定目的＃1：询问致癌信号传导，mTUPR和OI。特定目的＃2：确定介导的基因表达程序和在OIS和早期疾病原发性黑色素瘤期间由MTUPR维持。特定目的＃3：定义影响 NEVI和原发性疾病模型中MTUPR激活的激活。