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: 10300449
• 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/10300449
• 关键词: ARID1A gene; ApcMin/+ mice; Cancer Etiology; Cancer Model; Cell Compartmentation; Cell Nucleus; 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 该项目直接响应PAR-17-203“癌症中的细胞器间通讯”。一条新的途径是 一种被称为“mtDNA-IRDS”的途径，线粒体通过该途径向细胞核发送应激信号 调节干扰素刺激基因（ISG）的表达，这些基因通常与抗病毒药物相关。 免疫力在研究一种独特的小鼠mtDNA模型时，阐明了mtDNA-IRDS通路 由核编码的mtDNA包装因子TFAM的单倍不足引起的应激（即Tfam+/-小鼠）。 这些小鼠改变了线粒体和类核结构（染色质的线粒体版本）， 促进线粒体DNA释放到细胞质中。这些小鼠（以及从小鼠中分离的细胞）令人惊讶的特征是， 这种释放的mtDNA促进了先天免疫信号传导，导致一种独特的 ISG的一个子集，称为干扰素相关的DNA损伤抗性签名（IRDS）。IRDS 促进肿瘤细胞的化疗抗性。Tfam+/-条件增强了自发性肠 在人结直肠癌（CRC）的APCMin/+小鼠模型中的肿瘤发生和新的初步结果 显示了在CRC中通常突变肿瘤抑制因子ARID 1A（核的亚基）的敲除 SWI/SNF染色质重塑复合物）也诱导mtDNA-IRDS途径。因此， 该建议是mtDNA-IRDS途径增加了CRC中的肿瘤发生和/或化学抗性， 这将通过完成以下三个具体目标进行测试。目标1是了解如何 ARID 1A的突变导致mtDNA-IRDS途径诱导。目的2是阐明机制，通过 其中mtDNA-IRDS途径使用mtDNA介导的Tfam+/-模型增强核DNA修复， 细胞核信号传导目的3是研究mtDNA-IRDS通路在 使用Tfam+/-、APCMin/+和肠Arid 1a敲除的体内肿瘤发生和/或化学抗性 CRC小鼠模型和人CRC肿瘤样品。PARP 9-DTX 3L复合物是 将通过将这些CRC模型与Parp 9敲除杂交来测试体内肿瘤发生和化学抗性 小鼠CRC是男性和女性癌症相关死亡的主要原因， 对化疗产生了抗药性这一建议的意义在于它探讨了一部小说 由于mtDNA-IRDS通路激活导致的肿瘤发生和化疗耐药性的机制， 治疗靶向的潜力。