Investigating the role of nucleotide metabolism and AMPK signaling in melanoma metastasis

研究核苷酸代谢和 AMPK 信号在黑色素瘤转移中的作用

• 批准号: 10306350
• 负责人: Kristina Navrazhina
• 金额: $ 5.18万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-17 至 2022-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306350
• 关键词: Adenosine Monophosphate; Anabolism; Autophagocytosis; Biological Assay; Blood; Blood Circulation; Carbon; Catabolic Process; Catalytic Domain; Cell Survival; Cells; Data; Diagnosis; Distant; Environment; Enzymes; Epigenetic Process; Fluorescence Resonance Energy Transfer; Genetic; Hematogenous Spread; Homeostasis; Hypoxanthines; Immunocompromised Host; Investigation; Laboratories; Malignant Neoplasms; Melanoma Cell; Metabolic; Metabolism; Modeling; Molecular; Mus; NADP; Natural regeneration; Neoplasm Metastasis; Nodule; Nucleotide Metabolism Pathway; Nucleotides; Nutrient; Organ; Oxidative Stress; Pathway interactions; Patients; Pattern; Pharmacology; Primary Neoplasm; Process; Proliferating; Protein Kinase; Purines; Role; Signal Transduction; Site; Skin Cancer; Solid Neoplasm; Stress; Survival Rate; System; Therapeutic; Transplantation; United States; Up-Regulation; Visceral; Work; analog; arm; base; cancer cell; cancer diagnosis; clinically relevant; combat; genetic approach; in vivo; melanoma; mortality; new therapeutic target; nucleotide metabolism; patient derived xenograft model; predict clinical outcome; rational design; small hairpin RNA; subcutaneous; tool; tumor; tumor progression

PROJECT SUMMARY/ABSTRACT Metastasis, the spread of cancer cells from primary tumor to distant organs, accounts for 90% of solid tumor related mortality. The metabolic changes underlying this multistep cascade remain poorly understood. Recent work from our laboratory demonstrated that oxidative stress limits melanoma metastasis. Metastasizing cells utilize the one-carbon cycle to regenerate NADPH and combat oxidative stress. This increase in the NADPH- regenerating arm of one-carbon metabolism may limit the availability of substrates for other processes within the one-carbon cycle, including intermediates for purine biosynthesis. Consistent with this hypothesis, our preliminary data has shown that metastatic nodules have significantly higher levels of AICAR compared to subcutaneous tumors, suggesting a block in the de novo purine biosynthesis pathway. AICAR, an adenosine monophosphate analogue, is an allosteric activator of AMPK. We observe increased activation of AMPK in metastatic nodules compared to subcutaneous tumors. AMPK regulates the metabolic homeostasis by switching metabolism from anabolic to catabolic state thereby increasing cell survival in nutrient scarce conditions. I hypothesize that metastasizing cells preferentially rely on the salvage pathway and upregulate AMPK signaling, thereby switching to a catabolic metabolism to survive the hostile conditions of visceral organs. My proposal uses a clinically relevant model of melanoma metastasis in which patient-derived xenografts are transplanted into immunocompromised mice. Using this system, I will dissect the metabolic cascade and identify metabolic alterations that allow metastasizing melanoma cells to survive. In aim 1 of this proposal, I will ask whether metastasizing cells preferentially utilize the nucleotide salvage pathway during metastasis. In aim 2 of this proposal, I will investigate the role of AMPK signaling in promoting survival of metastasizing cells in circulation and upon colonization of distant organs. Successful completion of these aims will uncover the metabolic adaptations which allow metastasizing cells to survive and identify actionable targets to combat metastatic spread.

项目摘要/摘要 转移，即癌细胞从原发肿瘤扩散到远处器官，占实体肿瘤的90% 相关死亡率。这种多步骤级联反应背后的代谢变化仍然知之甚少。近期 我们实验室的工作表明，氧化应激限制了黑色素瘤的转移。转移细胞 利用一碳循环再生NADPH并对抗氧化应激。NADPH的增加- 单碳代谢的再生臂可能会限制用于其他过程的底物的可用性 一碳循环，包括嘌呤生物合成的中间体。与这一假设相一致，我们的 初步数据显示，转移性结节的AICAR水平明显高于 皮下肿瘤，提示新生的嘌呤生物合成途径受阻。AICAR，一种腺苷 单磷酸类似物，是AMPK的变构激活剂。我们观察到AMPK在 转移性结节与皮下肿瘤相比。AMPK通过开关调节代谢动态平衡 代谢从合成代谢到分解代谢，从而提高细胞在营养缺乏条件下的存活率。我 假设转移细胞优先依赖挽救途径并上调AMPK信号， 从而切换到分解代谢以在内脏器官的恶劣条件下生存。我的建议 使用临床相关的黑色素瘤转移模型，其中患者来源的异种移植物被移植 变成免疫功能低下的小鼠。使用这个系统，我将剖析新陈代谢级联并识别新陈代谢 允许转移的黑色素瘤细胞存活的变化。在这项提议的目标1中，我想问一下 转移细胞在转移过程中优先利用核苷酸挽救途径。在这个目标2中 我将研究AMPK信号在促进循环中转移细胞存活中的作用 以及对遥远器官的殖民。这些目标的成功完成将揭示新陈代谢 允许转移细胞存活并识别对抗转移的可操作靶点的适应 散开。

项目成果

The effect of subcutaneous brodalumab on clinical disease activity in hidradenitis suppurativa: An open-label cohort study.

• DOI: 10.1016/j.jaad.2020.05.007
• 发表时间: 2020-11
• 期刊: Journal of the American Academy of Dermatology
• 影响因子: 13.8
• 作者: Frew JW;Navrazhina K;Grand D;Sullivan-Whalen M;Gilleaudeau P;Garcet S;Ungar J;Krueger JG
• 通讯作者: Krueger JG