Mitochondria-to-Nucleus Signaling in Colorectal Cancer

结直肠癌中的线粒体到细胞核的信号转导

• 批准号: 10529300
• 负责人: Diana Clare Hargreaves
• 金额: $ 51.01万
• 依托单位: SALK INSTITUTE FOR BIOLOGICAL STUDIES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10529300
• 关键词: ARID1A gene; ApcMin/+ mice; Cancer Etiology; Cancer Model; Cell Compartmentation; Cell Nucleus; Cell Separation; Cells; Cellular Structures; Cessation of life; Chemoresistance; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Colonic Neoplasms; Colorectal Cancer; Communication; Complex; Cytoplasm; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; Data; Disease; Event; Exhibits; Gene Expression Profile; Genes; Genomics; Goals; Heterozygote; Homeostasis; Human; Immune signaling; Immunity; In Vitro; Inherited; Interferons; Intestines; Investigation; Knock-out; Knockout Mice; Lead; MC38; MCC gene; Malignant Neoplasms; Mediating; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Morphology; Mothers; Mus; Mutate; Mutation; Nature; Nuclear; Organelles; PARP9 gene; Pathway interactions; Resistance; Role; Sampling; Signal Pathway; Signal Transduction; Stress; Structure; Testing; Tumor Suppressor Proteins; Up-Regulation; Woman; antiviral immunity; cancer cell; chemotherapy; chromatin remodeling; effective therapy; enzyme model; human model; in vivo; intestinal tumorigenesis; member; men; mouse model; neoplastic cell; novel; null mutation; oxidation; programs; repaired; restriction enzyme; therapeutic target; tumor; tumorigenesis; virtual

PROJECT SUMMARY This project responds directly to PAR-17-203 “Inter-organelle Communication in Cancer.” A new pathway was discovered called the “mtDNA-IRDS” pathway, through which mitochondria send a stress signal to the nucleus to regulate expression of interferon-stimulated genes (ISGs), which are usually associated with antiviral immunity. The mtDNA-IRDS pathway was elucidated during investigations of a unique mouse model of mtDNA stress caused by haploinsufficiency of the nucleus-encoded mtDNA-packaging factor TFAM (i.e. Tfam+/- mice). These mice have altered mitochondria and nucleoid structures (the mitochondrial version of chromatin) that promotes release of mtDNA into the cytoplasm. The surprising feature of these mice (and cells isolated from them) is that this released mtDNA promotes innate immune signaling, resulting in upregulation of a unique subset of ISGs known as the Interferon-Related DNA-damage resistance Signature (IRDS). The IRDS promotes chemotherapy resistance of tumor cells. The Tfam+/- condition enhances spontaneous intestinal tumorigenesis In the APCMin/+ mouse model of human colorectal cancer (CRC) and new preliminary results show that knock-out of the tumor suppressor commonly mutated in CRC, ARID1A (a subunit of the nuclear SWI/SNF chromatin remodeling complex) also induces the mtDNA-IRDS pathway. Thus, the main premise of this proposal is that the mtDNA-IRDS pathway increases tumorigenesis and/or chemoresistance in CRC, which will be tested through completion of the following three Specific Aims. Aim 1 is to understand how mutations in ARID1A lead to mtDNA-IRDS pathway induction. Aim 2 is to elucidate the mechanism through which the mtDNA-IRDS pathway enhances nuclear DNA repair using the Tfam+/- model of mtDNA-mediated, mitochondria-to-nucleus signaling. Aim 3 is to investigate the role of the mtDNA-IRDS pathway in tumorigenesis and/or chemoresistance in vivo using the Tfam+/-, APCMin/+ and intestinal Arid1a knock-out mouse models of CRC and human CRC tumor samples. That the PARP9-DTX3L complex is a major driver of tumorigenesis and chemoresistance in vivo will be tested by crossing these CRC models to Parp9 knock-out mice. CRC is a leading cause of cancer-related deaths in both men and women, and treatment of this disease is plagued by resistance to chemotherapy. The significance of this proposal is that it probes a novel mechanism of tumorigenesis and chemoresistance due to mtDNA-IRDS pathway activation that has the potential for therapeutic targeting.

项目摘要 该项目直接对17-203 PAR响应“癌症中的轨道间通信”。一条新途径是 被发现称为“ mtDNA-ridgs”途径，线粒体通过该途径向核发出应力信号 调节干扰素刺激的基因（ISGS）的表达，这些基因通常与抗病毒有关 免疫。在研究MTDNA的独特小鼠模型期间阐明了mtDNA-drys途径 核编码的mtDNA包装因子TFAM（即TFAM +/-小鼠）引起的应力。 这些小鼠改变了线粒体和核苷结构（染色质的线粒体版本） 促进mtDNA释放到细胞质中。这些小鼠的令人惊讶的特征（以及从中分离出来的细胞 他们）是，这种释放的mtDNA促进了先天的免疫信号传导，从而导致独特的上调 ISG的子集被称为干扰素相关的DNA破坏抗性特征（IRDS）。 IRDS 促进肿瘤细胞的化学疗法耐药性。 TFAM +/-条件增强了自发肠 人类结直肠癌（CRC）APCMIN/+小鼠模型的肿瘤发生和新的初步结果 表明通常在CRC中突变的肿瘤抑制剂ARID1A（核的亚基） SWI/SNF染色质重塑络合物）还诱导mtDNA-drigts途径。那是主要的前提 该提议是mtDNA-dREDS途径增加了CRC中的肿瘤发生和/或化学抗性， 将通过完成以下三个特定目标来测试。目标1是了解如何 ARID1A中的突变导致mtDNA-dREDS途径诱导。目标2是通过 mtDNA-irds途径使用mtDNA介导的TFAM +/-模型增强了核DNA修复 线粒体到核信号传导。 AIM 3是研究mtDNA-rids途径在 使用TFAM +/-，APCMIN/+和肠ARID1A敲除，在体内进行肿瘤发生和/或化学抗性 CRC和人CRC肿瘤样品的小鼠模型。 PARP9-DTX3L复合物是 通过将这些CRC模型跨越PARP9敲除，将测试体内肿瘤发生和化学抗性 老鼠。 CRC是男性和女性与癌症相关死亡的主要原因，治疗这种疾病 受到化学疗法的抗性困扰。该提议的意义在于它探究了新颖的 肿瘤发生和化学抗性的机理，该杂志是由于mtDNA-dREDS途径激活而具有的机制 治疗靶向的潜力。