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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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要该项目直接响应 PAR-17-203“癌症中的细胞器间通讯”。一条新途径是发现了称为“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。在研究独特的 mtDNA 小鼠模型期间阐明了 mtDNA-IRDS 通路由核编码 mtDNA 包装因子 TFAM 的单倍体不足引起的应激（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 mtDNA 释放到细胞质中。这些小鼠（以及从其中分离出的细胞）的令人惊讶的特征他们）是这种释放的线粒体DNA促进先天免疫信号传导，导致独特的上调 ISG 的子集，称为干扰素相关 DNA 损伤抵抗特征 (IRDS)。 IRDS 促进肿瘤细胞的化疗耐药性。 Tfam+/- 条件增强自发性肠道人结直肠癌 (CRC) APCMin/+ 小鼠模型中的肿瘤发生和新的初步结果表明敲除 CRC 中常见突变的肿瘤抑制基因 ARID1A（核细胞亚基） SWI/SNF 染色质重塑复合物）也诱导 mtDNA-IRDS 途径。因此，主要前提是该提议认为 mtDNA-IRDS 途径会增加 CRC 的肿瘤发生和/或化疗耐药性，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 ARID1A 突变导致 mtDNA-IRDS 途径诱导。目标 2 是通过以下方式阐明其机制： mtDNA-IRDS 途径使用 mtDNA 介导的 Tfam+/- 模型增强核 DNA 修复，线粒体到细胞核的信号传导。目标 3 是研究 mtDNA-IRDS 通路在使用 Tfam+/-、APCMin/+ 和肠道 Arid1a 敲除研究体内肿瘤发生和/或化疗耐药性 CRC 小鼠模型和人类 CRC 肿瘤样本。 PARP9-DTX3L 复合体是主要驱动因素将通过将这些 CRC 模型与 Parp9 敲除模型交叉来测试体内肿瘤发生和化疗耐药性老鼠。结直肠癌是男性和女性癌症相关死亡的主要原因，而这种疾病的治疗受到化疗耐药性的困扰。该提案的意义在于它探索了一种新颖的 mtDNA-IRDS 通路激活导致肿瘤发生和化疗耐药的机制治疗靶向的潜力。