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

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

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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?

概括负责维持正常代谢的线粒体网络的失调是一种建立了癌症的标志和肿瘤发生的早期事件。细胞代谢的破坏导致活性氧（ROS）的积累和触发不良的信号传导破坏代谢平衡，该平衡可以建立抗肿瘤和/或抗治疗的表型。在这方面，表现出的雌激素受体阳性（ER+）乳腺癌的亚组已经确定了ROS水平升高和由于内分泌治疗引起的高风险。我们最近发现了一个以锰超氧化为中心的新型线粒体信号轴裂隙酶（MNSOD），当赖氨酸68（K68-AC）的乙酰化（AC）状态发生时，破坏了细胞代谢，导致异常ROS水平（Zhu，Nature Commun。，2019年）。另外，乳房表达MNSOD-K68-AC模拟突变体（MNSODK68Q）的癌细胞暴露增加了HIF2α （已知可以促进干性特性），增加了Sox2和Oct4（两个已建立的干细胞生物标志物），导致致癌性和PAN耐药性表型（PANR）通常为药物用于腔内B乳房恶性肿瘤，使细胞代谢的破坏重编程肿瘤表现出谱系可塑性表型。根据我们的新数据，我们最近出版（Zhu等人，大自然社区。 2019年），以及其他人的工作，假设MNSOD生物学失调，由于异常/MNSOD-K68-AC水平增加，破坏了正常的细胞和线粒体代谢。这通过升高的HIF2α启动代谢重编程，导致细胞干性介导的肿瘤 - 腐蚀性和/或PANR表型。这，我们试图进一步探索 MNSOD-K68-AC破坏细胞代谢并促进类样表型，导致致癌性和/或PANR。最后，将gc4419暴露，一种化学SOD排毒模仿，扭转致癌和/或PANR表型？