Mitochondria-to-Nucleus Signaling in Colorectal Cancer

项目总结 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 这一发现被称为“线粒体DNA-IRDS”途径，线粒体通过该途径向细胞核发送压力信号。 调节干扰素刺激基因(ISGs)的表达，这些基因通常与抗病毒药物有关 豁免权。线粒体DNA-irds通路是在一种独特的mtDNA小鼠模型的研究中阐明的。 由核编码的线粒体DNA包装因子TFAM(即Tfam/-小鼠)单倍性不足引起的应激。 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进入细胞质的释放。这些小鼠令人惊讶的特征(以及从 它们)是这种释放的mtDNA促进先天性免疫信号，导致一种独特的 ISG的子集，称为干扰素相关的DNA损伤抗性特征(IRD)。红绿灯 促进肿瘤细胞的化疗耐药性。TFAM/-状态增强自发性肠道 APCMin/小鼠结直肠癌模型的致瘤性及新的初步结果 显示了在CRC、ARID1A(核亚单位)中常见突变肿瘤抑制基因的敲除 SWI/SNF染色质重塑复合体)也诱导了mtDNA-IRDS途径。因此，主要的前提是 这一建议是mtDNA-IRDS途径增加了结直肠癌的肿瘤形成和/或化疗耐药性， 将通过完成以下三个具体目标来检验这一点。目标1是了解如何 ARID1A基因突变导致线粒体DNA-IRDS途径的诱导。目标2是通过以下途径阐明其作用机制 其中mtDNA-IRDS途径利用mtDNA介导的Tfam/-模型促进核DNA修复， 线粒体到细胞核的信号传递。目的3研究线粒体DNA-IRDS通路在人类免疫缺陷中的作用。 利用Tfam/-、APCMin/和肠道ARID1A基因敲除的肿瘤发生和/或体内化疗耐药 小鼠结直肠癌模型和人结直肠癌肿瘤标本。PARP9-DTX3L复合体是 通过将这些结直肠癌模型与Parp9基因敲除杂交来测试体内的肿瘤发生和化疗耐药性 老鼠。结直肠癌是导致男性和女性癌症相关死亡的主要原因，这种疾病的治疗 正受到化疗耐药性的困扰。这项提议的意义在于它探索了一部小说 线粒体DNA-IRDS途径激活导致肿瘤发生和化疗耐药的机制 潜在的治疗靶向。

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.