MNSOD ACETYLATION PROMOTES CANCER STEM CELL PHENOTYPES IN BREAST CANCER

项目摘要 乳腺癌的侵袭性表型的特征是逃避免疫的能力增加， 监视和产生转移。我们的研究小组最近发现转移性乳腺癌细胞 表达高水平的乙酰化超氧化物歧化酶2（SOD 2K 68 Ac）积累了拟南芥衍生的 活性氧（mtROS）和促进缺氧诱导因子2α（HIF 2 α）的稳定，涉及 肿瘤侵袭性HIF 2 α还调节与免疫保护相关的基因，包括 程序性死亡配体1（PDL 1），被广泛认为是引发癌症免疫逃避的分子 细胞因此，我们建议研究（1）SOD 2K 68 Ac的积累是否通过HIF 2 α促进PDL 1上调 （2）如果SOD 2K 68 Ac/HIF 2 α促进乳腺癌细胞的免疫逃避和转移， 体内使用小鼠模型;和（3）如果有一个乳腺癌妇女亚组表现出 SOD 2K 68 Ac/HIF 2 α分子特征与高PDL 1表达和免疫治疗抗性相关我们 我希望能发现一种新的癌症免疫逃避机制，可以有针对性地提高治疗效果。 治疗表现出SOD 2K 68 Ac分子标记的乳腺癌侵袭性表型的方法。的 拟议的转化研究将由科埃略博士在马塞洛·博尼尼博士的指导下进行 （主要导师）、Leonidas Platanias博士（共同导师）和Massimo Cristofanilli博士（临床共同导师）。所有 导师在翻译过程中具有科学成就、创新和领导力的模范记录 癌症的治疗和诊断。除了这项应用的科学目标，我们希望博士。 科埃略将完成临床研究，领导，写作和管理方面的多学科培训 在癌症免疫生物学中建立独立的职业生涯至关重要。

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.