Mitophagy-Mediated Cell Death in Mammary Tumorigenesis

乳腺肿瘤发生中线粒体自噬介导的细胞死亡

• 批准号: 10277900
• 负责人: Zachary T. Schafer
• 金额: $ 39.86万
• 依托单位: UNIVERSITY OF NOTRE DAME
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10277900
• 关键词: 3-Dimensional; Address; Anchorage-Independent Growth; Anoikis; Antioxidants; Applications Grants; Biological; Biological Assay; Breast Cancer Cell; Breast Cancer Patient; Cancer Patient; Cancerous; Caspase; Cell Culture Techniques; Cell Death; Cell Survival; Cells; Cessation of life; Complex; Data; Development; Disease; Disseminated Malignant Neoplasm; Distant; Epithelial Cells; Exposure to; Extracellular Matrix; FDA approved; Integrins; Investigation; Knowledge; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Metastatic to; Mitochondria; Molecular; Molecular Analysis; Necrosis; Neoplasm Metastasis; Nude Mice; Organ; Outcome; Pathway interactions; Patients; Phosphotransferases; Prognosis; Protein Kinase; Proteins; RIPK1 gene; Reactive Oxygen Species; Receptor Inhibition; Receptor Signaling; Regulation; Role; Signal Transduction; Therapeutic; Therapeutic Intervention; Tumor stage; breast cancer progression; cancer cell; cancer survival; combat; design; in vivo; insight; intravenous injection; mortality; new therapeutic target; novel; novel strategies; novel therapeutic intervention; programs; therapeutic development; tumor; tumor progression; tumorigenesis

Project Summary Background: The metastasis of cancerous cells to distant and vital organs is responsible for in excess of 90% of cancer mortalities. Given this extraordinarily high mortality rate, there is a significant need for the development of novel therapeutic approaches that either eliminate metastatic cancer cells or eradicate incipient cancer cells prior to metastatic dissemination. An important barrier to tumor progression and metastasis is anoikis, a caspase- dependent cell death program induced by loss of integrin-mediated attachment to extracellular matrix (ECM). However, it has become clear that ECM-detachment can induce anoikis-independent mechanisms that can compromise cell viability. More specifically, we have discovered that detachment of non-cancerous epithelial cells from ECM triggers a significant elevation in the levels of reactive oxygen species (ROS) which compromises cell survival in an anoikis-independent fashion. The understanding of the cellular changes that contribute to the elevation of ROS during ECM-detachment remains rudimentary and the strategies utilized by cancer cells to combat ROS during ECM-detachment are insufficiently explored. Therefore, these points represent significant knowledge gaps that this grant proposal aims to address. Discernment of mechanistic information regarding the links between ECM-detachment, ROS, and cell survival could provide targets for the design of the therapeutic approaches aimed at specifically eliminating ECM-detached cancer cells; an outcome that may have significant impact for patients with metastatic disease. Objective/hypothesis: In aggregate, our preliminary studies have unveiled a novel cell death mechanism (with a tumor suppressive function) that compromises the viability of ECM-detached cells: the induction of mitophagy as consequence of RIPK1 signaling. As such, these data have motivated our central hypothesis that RIPK1- mediated mitophagy during ECM-detachment functions as a barrier to breast cancer progression. Specific Aim I: To elucidate the molecular mechanism by which ECM-detachment promotes RIPK1-dependent mitophagy and initiates cell death. Specific Aim II: To assess the capacity of RIPK1-mediated mitophagy to antagonize tumor formation in vivo and to evaluate antioxidant inhibition as a novel strategy to limit tumorigenesis in cancers that are deficient in RIPK1-mediated mitophagy Anticipated Outcomes: Following the completion of these studies, we will have accumulated significant mechanistic knowledge regarding the relationship between ECM-detachment, RIPK1 mitophagy, and cell death. Thus, the completion of these studies will unveil fundamental biological insights regarding cancer cell survival during ECM-detachment that may ultimately lead to the development of therapeutic approaches to limit the dissemination of breast cancer cells.

项目摘要 背景：癌细胞转移到遥远和重要器官的转移，造成超过90％ 癌症死亡率。鉴于这种非常高的死亡率，对发展有很大的需求 消除转移性癌细胞或根除初期癌细胞的新型治疗方法 在转移性传播之前。肿瘤进展和转移的重要障碍是Anoikis，caspase- 依赖性细胞死亡程序是由整联蛋白介导的附着在细胞外基质（ECM）上引起的。 但是，很明显，ECM检测可以诱导与Anoikis无关的机制，可以 损害细胞生存能力。更具体地说，我们发现非癌性上皮的分离 ECM的细胞触发了损害的活性氧（ROS）水平的显着升高 细胞生存以独立于Anoikis的方式。对有助于细胞变化的理解 ECM核能期间ROS的升高仍然是基本的，癌细胞使用的策略 在ECM解决过程中的战斗ROS不足。因此，这些观点代表着重要的 该赠款提案旨在解决的知识差距。有关机械信息的识别 ECM详细信息，ROS和细胞存活之间的联系可以为设计的设计提供目标 旨在专门消除ECM解决的癌细胞的方法；可能具有重要意义的结果 对转移性疾病患者的影响。 客观/假设：在总体上，我们的初步研究揭示了一种新型的细胞死亡机制（带有 肿瘤抑制功能）损害了ECM解决细胞的生存能力：线粒体的诱导 由于RIPK1信号传导。因此，这些数据激发了我们的中心假设，即RIPK1- ECM延伸过程中介导的线粒体是乳腺癌进展的障碍。 特定目的I：阐明ECM核能促进RIPK1依赖性的分子机制 线粒体并引发细胞死亡。 特定目的II：评估RIPK1介导的线粒体在体内拮抗肿瘤形成的能力 并评估抗氧化剂抑制作用，作为限制缺乏癌症的肿瘤发生的新策略 RIPK1介导的线粒体 预期的结果：这些研究完成后，我们将积累大量 关于ECM核能，RIPK1线粒能和细胞死亡之间关系的机械知识。 因此，这些研究的完成将公布有关癌细胞的基本生物学见解 ECM结束期间的生存最终可能导致治疗方法的发展 限制乳腺癌细胞的传播。