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

• 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
• 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

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。细胞新陈代谢的破坏 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）。另外，丰胸 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 - 意味着细胞代谢的破坏会重新编程肿瘤 表现出谱系可塑性表型。根据我们的新数据，我们最近发表的文章（Zhu et al, 自然交流。 2019）以及其他人的工作，假设 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 代谢。这通过 HIF2α 水平的增加启动代谢重编程，从而导致细胞 干性介导的肿瘤允许和/或 PanR 表型。因此，我们寻求进一步探索如何 MnSOD-K68-Ac 会破坏细胞代谢并促进干细胞样表型，从而导致 致癌性和/或 PanR。最后，GC4419 是否会暴露，这是一种化学 SOD 解毒模拟物， 逆转致癌和/或 PanR 表型？