MNSOD ACETYLATION PROMOTES CANCER STEM CELL PHENOTYPES IN BREAST CANCER

MNSOD 乙酰化促进乳腺癌干细胞表型

• 批准号: 10380372
• 负责人: Marcelo G Bonini
• 金额: $ 12.56万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-14 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10380372
• 关键词: Abbreviations; Acetylation; Achievement; Breast Cancer Cell; Cancer Patient; Cells; Characteristics; Chemoresistance; Clinical; Clinical Research; Diagnostic; Disease; Exhibits; Genes; Goals; Hypoxia Inducible Factor; Immune; Immune Evasion; Immunologic Surveillance; Immunotherapy; Lead; Leadership; Link; Lysine; Malignant Neoplasms; Mammary Neoplasms; Mentors; Mentorship; Metastatic breast cancer; Mitochondria; Molecular Profiling; Neoplasm Metastasis; Phenotype; Reactive Oxygen Species; Records; Recurrence; Resistance; Risk; SOD2 gene; Subgroup; Therapeutic; Training; Translational Research; Treatment Failure; Tumor Escape; Up-Regulation; Woman; Writing; base; cancer cell; cancer immunobiology; cancer stem cell; career; conventional therapy; improved; in vivo; innovation; malignant breast neoplasm; mouse model; multidisciplinary; programmed cell death ligand 1; stem cells; stem-like cell; stemness; therapeutic target; translational pipeline; tumor

PROJECT SUMMARY Aggressive phenotypes of breast cancer are characterized by increased capacity of evading immune surveillance and generating metastasis. Our groups recently described that metastatic breast cancer cells expressing high levels of acetylated superoxide dismutase 2 (SOD2K68Ac) accumulate mitochondria-derived reactive oxygen species (mtROS) and promote stabilization of hypoxia-inducible factor 2α (HIF2α), involved tumor aggressiveness. HIF2α also regulates genes associated with immune protection, including the programmed death-ligand 1 (PDL1) that is widely recognized as a molecule eliciting immune evasion in cancer cells. Hence, we propose to investigate (1) if accumulation of SOD2K68Ac promotes PDL1 upregulation via HIF2α in breast cancer cells; (2) if SOD2K68Ac/HIF2α promotes mammary cancer immune evasion and metastasis in vivo using mouse model; and (3) if there is a subgroup of women with breast cancer that exhibits SOD2K68Ac/HIF2α molecular signature correlating with high PDL1 expression and immunotherapy resistance. We expect to identify a new mechanism of cancer immune evasion that can be targeted to improve therapeutic approaches to treat aggressive phenotypes of breast cancer exhibiting SOD2K68Ac molecular signature. The proposed translational research will be conducted by Dr. Coelho under the mentorship of Dr. Marcelo Bonini (primary mentor), Dr. Leonidas Platanias (co-mentor) and Dr. Massimo Cristofanilli (clinical co-mentor). All mentors have exemplary records of scientific achievement, innovation and leadership in the translational pipeline of cancer therapeutics and diagnostics. In addition to the scientific goal of this application, we expect that Dr. Coelho will accomplish a multidisciplinary training in clinical research, leadership, writing and management essential to establish an independent career in cancer immunobiology.

项目摘要 乳腺癌的侵略性表型的特征是逃避免疫的能力增加 监视和产生转移。我们的小组最近描述了转移性乳腺癌细胞 表达高水平的乙酰化超氧化物歧化酶2（SOD2K68AC）积累了线粒体衍生的 活性氧（MTROS）并促进缺氧诱导因子2α（HIF2α）的稳定，涉及 HIF2α还调节与免疫保护相关的基因，包括 被广泛认为是癌症中免疫进化的分子的程序性死亡配体1（PDL1） 细胞。因此，我们建议研究（1）如果SOD2K68AC的积累促进PDL1通过HIF2α上调 在乳腺癌细胞中； （2）如果SOD2K68AC/HIF2α促进乳腺癌免疫进化和转移 使用鼠标模型的体内； （3）如果有乳腺癌的女性亚组 SOD2K68AC/HIF2α分子特征与高PDL1表达和免疫疗法抗性相关。我们 期望确定一种可以针对改善治疗的癌症免疫进化的新机制 治疗表现出SOD2K68AC分子特征的乳腺癌侵袭性表型的方法。这 拟议的翻译研究将由Coelho博士在Marcelo Bonini博士的心态下进行 （主要导师），莱昂达斯·普拉塔尼亚斯博士（Co-Incertor）和Massimo Cristofanilli博士（临床同事）。全部 导师在转化管道中拥有科学成就，创新和领导力的典范记录 癌症治疗和诊断。除了该应用程序的科学目标外，我们还希望博士 Coelho将在临床研究，领导，写作和管理方面完成多学科培训 建立癌症免疫生物学独立职业至关重要。