MnSOD-K68-Ac reprograms a lineage plasticity switch / stemness in ER+ breast malignancies

MnSOD-K68-Ac 重新编程 ER 乳腺恶性肿瘤中的谱系可塑性开关/干性

基本信息

批准号：
10541193
负责人：
David Gius
金额：
$ 36.08万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-09 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10541193
关键词：
Acetylation Adjuvant Therapy Biological Markers Biology Breast Breast Cancer Cell Cell physiology Cells Cellular Metabolic Process ChIP-seq Chemicals Cisplatin Clustered Regularly Interspaced Short Palindromic Repeats Compensation Complex Data Doxorubicin Drug Metabolic Detoxication Endocrine Equilibrium Estrogen receptor positive Event Exhibits Exposure to Fatty acid glycerol esters Fulvestrant Genes Grant Knock-out Lead Link Lysine MCF7 cell Malignant Neoplasms Mammary Neoplasms Measurement Measures Mediating Metabolic Metabolism Mitochondria Modeling Nature Oncogenic Pathway interactions Peroxidases Phenotype Physiological Post-Translational Protein Processing Property Publications Reactive Oxygen Species Recurrence Reporter Resistance Risk SOD2 gene Selective Estrogen Receptor Modulators Signal Transduction Sirtuins Stains Subgroup Superoxides Systemic Therapy T47D Tamoxifen Techniques Testing Time Tissue Microarray Tumor Promoters Woman Work Xenograft Model breast malignancies cancer cell high risk hormone therapy in vivo knock-down mammary mimetics mitochondrial metabolism monomer mouse model mutant neoplastic cell new therapeutic target novel patient derived xenograft model permissiveness prevent programs public database response small hairpin RNA stem stem cell biomarkers stem-like cell stemness targeted treatment therapy resistant tissue culture transcriptome sequencing tumor tumorigenesis tumorigenic

项目摘要

SUMMARY The dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolism leads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling that disrupts metabolic balance, which can establish a tumorigenic and/or therapy resistant phenotype. In this regard, a subgroup of estrogen receptor-positive (ER+) breast malignancies, which exhibit increased ROS levels and a high risk of recurrence due to endocrine therapy, has been identified. We recently found a novel mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD), which when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cell metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, breast cancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2α (known to promote stemness-like properties), increased SOX2 and Oct4 (two established stem cell biomarkers), leading to oncogenicity and pan resistance phenotype (PanR) to agents commonly used in luminal B breast malignancies-implying that disruption of cell metabolism reprograms tumors to exhibit a lineage plasticity phenotype. Based on our new data, our recent publication (Zhu et al, Nature Commun. 2019), and work by others, it is hypothesized that dysregulated MnSOD biology, due to aberrant/increased MnSOD-K68-Ac levels, disrupts normal cellular and mitochondrial metabolism. This initiates metabolic reprogramming, via increased levels of HIF2α, leading to a cell stemness-mediated tumor-permissive and/or PanR phenotype. Thus, we seek to further explore how MnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype, leading to oncogenicity and/or PanR. Finally, will GC4419 exposure, a chemical SOD detoxification mimic, reverse the oncogenic and/or PanR phenotypes?

概括负责维持正常新陈代谢的线粒体网络的失调是一个确定了癌症的标志和肿瘤发生的早期事件。导致活性氧 (ROS) 积累并触发适应不良信号破坏代谢平衡，从而形成致瘤和/或治疗耐药表型。在这方面，雌激素受体阳性（ER+）乳腺恶性肿瘤的一个亚组，表现出已发现内分泌治疗导致 ROS 水平升高和复发风险较高。我们最近发现了一种以超氧化锰为中心的新型线粒体信号轴歧化酶 (MnSOD)，当赖氨酸 68 (K68-Ac) 的乙酰化 (Ac) 状态发生改变时，会破坏细胞代谢，导致 ROS 水平异常（Zhu，Nature Commun.，2019）。表达 MnSOD-K68-Ac 模拟突变体 (MnSODK68Q) 的癌细胞表现出 HIF2α 增加（已知可促进干性样特性），增加 SOX2 和 Oct4（两种已建立的干细胞生物标志物），通常导致致癌性和对药物的泛耐药表型（PanR）用于管腔 B 型乳腺恶性肿瘤——表明细胞代谢的破坏会重新编程肿瘤根据我们的新数据，我们最近发表的文章（Zhu et al, Nature Commun. 2019）以及其他人的工作，重新认识到 MnSOD 生物学失调，由于 MnSOD-K68-Ac 水平异常/增加，会破坏正常细胞和线粒体这会通过 HIF2α 水平的增加启动代谢重编程，从而产生细胞。因此，我们寻求进一步探索如何实现干性介导的肿瘤许可和/或 PanR 表型。 MnSOD-K68-Ac 会破坏细胞代谢并促进干细胞样表型，从而导致最后，GC4419（一种化学 SOD 解毒模拟物）是否会暴露？逆转致癌和/或 PanR 表型？