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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.

项目总结