A metabolic decision point in the progression of lymphoid malignancies

淋巴恶性肿瘤进展中的代谢决策点

• 批准号: 10258308
• 负责人: Stefan M Schieke
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10258308
• 关键词: Affect; Automobile Driving; Behavior; Biology; Cell Line; Cells; Chemicals; Chronic Lymphocytic Leukemia; Citric Acid Cycle; Clinical; Disease; Disease Progression; Environment; Exposure to; Generations; Genes; Genetic; Glucose; Habitats; Herbicides; Human; In Vitro; Infiltration; Knowledge; Label; Lactate Transporter; Link; Lymphoblastic Leukemia; Lymphoma; Malignant lymphoid neoplasm; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Non-Hodgkin' s Lymphoma; Nutrient; Organ; Organ Transplantation; Oxidation-Reduction; Patients; Pharmacology; Phenotype; Play; Prognosis; Property; Pyruvate; Pyruvate Metabolism Pathway; Reactive Oxygen Species; Risk; Role; Scheme; Signal Transduction; Solid; Stable Isotope Labeling; Survival Rate; Testing; Therapeutic; Tissues; Transcriptional Regulation; Translating; Xenograft Model; Xenograft procedure; advanced disease; agent orange; cancer cell; cell motility; chronic lymphocytic leukemia cell; design; effective therapy; flexibility; glucose metabolism; hazard; improved; in vivo; innovation; insight; leukemia/lymphoma; lymphocyte trafficking; malignant lymphocyte; migration; military service; military veteran; mouse model; novel; novel therapeutics; oxidation; preference; programs; pyruvate carrier; therapeutic target; transcriptome; transcriptome sequencing; treatment strategy; tumor progression

Despite recent therapeutic advances, curing lymphoid malignancies such as non-Hodgkin lymphoma and lymphoid leukemia remains a clinical challenge. While critical for prognosis, the mechanisms regulating malignant lymphocyte trafficking, migration, and solid organ infiltration are incompletely understood. Metabolic flexibility plays a critical role during cancer progression aligning metabolic requirements of cancer cells with specific tissue environments. In lymphoid cancers, however, little is known about the impact of metabolic programming on cell migration and disease progression. Our preliminary studies demonstrate that malignant lymphocyte migration and solid organ infiltration are tightly connected to cellular metabolic preferences. We discovered that T- and B-lymphoid cancer cell migration and organ infiltration in xenograft models is determined by mitochondrial reactive oxygen species (mROS) through analysis of mROSlow and mROShigh states. This innovative strategy permits us to isolate cells with different migratory potentials to dissect fuel preferences of the “enhanced migratory potential”-mROShigh (EMP-mROShigh) state. We identified glucose as an essential fuel driving migration through activation of mROS/HIF-1a signaling. Initial 13C-glucose tracing studies showed reprogrammed glucose metabolism in migrating cells. Reduced pyruvate oxidation in the TCA cycle and enhanced lactate generation promoted migration through HIF-1a signaling. These results support our hypothesis that the branch point in pyruvate flux is a critical “metabolic decision point” controlling malignant lymphocyte migration and organ infiltration. We predict that dynamic shifts in pyruvate flux between mitochondrial oxidation and conversion into lactate control migratory and infiltrative potential through transcriptional regulation of mROS/HIF-1a-dependent cellular migration programs. The following specific aims will test this hypothesis: Aim 1. Establish the role of pyruvate flux as a decision point to control malignant lymphocyte migration and infiltration. We will test the hypothesis that a shift in pyruvate metabolism between TCA cycle oxidation and reduction to lactate represents a critical checkpoint of malignant lymphocyte migration and solid organ infiltration through modulation of mROS/HIF-1a signaling. Aim 2. Identify the molecular mechanisms for control of migratory behavior by the metabolic decision point. This aim will test the hypothesis that pyruvate flux as a metabolic decision point controls migration through transcriptional regulation of mROS/HIF1a-dependent cellular migration programs. We will perform RNAseq analyses of CLL cells followed by functional analyses to identify genes translating metabolic reprogramming into migration potential. Aim 3: Dissect fuel preferences and metabolic reprogramming of enhanced migratory cancer cells through in vivo metabolic tracing in CLL patients. We will test the hypothesis that the EMP-mROShigh cells in CLL patients in vivo show reprogrammed glucose and TCA cycle metabolism analogous to the in vitro phenotype. Patients will be infused with 13C-labeled nutrients to determine pyruvate flux and TCA cycle fueling in “enhanced migratory potential” CLL cells in their in vivo habitat critical to help define therapeutic strategies targeting the EMP-mROShigh phenotype in patients. Elucidating the metabolic underpinnings of malignant lymphocyte migration and solid organ infiltration will provide important insight into disease biology and uncover novel treatment strategies for lymphoid malignancies such as CLL which are highly relevant to the Veteran population due to their link to Agent Orange and other herbicide exposures during military service.

尽管最近的治疗进展，治疗淋巴恶性肿瘤，如非霍奇金淋巴瘤和 淋巴性白血病仍然是临床上的挑战。虽然对预后至关重要，但调节机制 恶性淋巴细胞运输、迁移和实体器官浸润尚不完全清楚。代谢 灵活性在癌症进展期间起着关键作用， 特定的组织环境。然而，在淋巴癌中，对代谢性肿瘤的影响知之甚少。 编程细胞迁移和疾病进展。我们的初步研究表明， 淋巴细胞迁移和实体器官浸润与细胞代谢偏好紧密相关。我们 发现异种移植模型中的T淋巴和B淋巴癌细胞迁移和器官浸润， 通过线粒体活性氧（mROS）通过分析mROSlow和mROShigh确定 states.这种创新的策略使我们能够分离出具有不同迁移潜力的细胞， “增强的迁移潜力”-mROShigh（EMP-mROShigh）状态的偏好。我们将葡萄糖鉴定为 通过激活mROS/HIF-1a信号传导驱动迁移的重要燃料。初始13 C-葡萄糖示踪 研究表明迁移细胞中的葡萄糖代谢发生了重组。TCA中丙酮酸氧化减少 循环和增强的乳酸产生通过HIF-1a信号传导促进迁移。这些结果支持 我们假设丙酮酸流量的分支点是控制恶性肿瘤的关键“代谢决定点”， 淋巴细胞迁移和器官浸润。我们预测，丙酮酸流量的动态变化， 线粒体氧化和转化为乳酸控制迁移和渗透潜力， mROS/HIF-1a依赖性细胞迁移程序的转录调控。以下具体目标 将检验这个假设： 目标1.建立丙酮酸流量作为控制恶性淋巴细胞的决定点的作用 迁移和渗透。我们将检验丙酮酸代谢在TCA循环之间的转变 氧化和还原为乳酸代表恶性淋巴细胞迁移和固体的关键检查点。 通过调节mROS/HIF-1a信号传导的器官浸润。 目标2.通过代谢决定确定控制迁移行为的分子机制 点这一目标将检验丙酮酸通量作为代谢决定点控制迁移的假设 通过转录调节mROS/HIF 1a依赖的细胞迁移程序。我们将执行 CLL细胞的RNAseq分析，随后进行功能分析以鉴定翻译代谢产物的基因 重新编程为迁移潜力。 目标3：剖析增强迁移癌细胞的燃料偏好和代谢重编程 通过CLL患者体内代谢追踪。我们将检验EMP-mROShigh细胞 在CLL患者中，体内显示与体外类似的重编程葡萄糖和TCA循环代谢 表型患者将输注13 C标记的营养物，以确定丙酮酸通量和TCA循环燃料 在“增强的迁移潜力”的CLL细胞在其体内栖息地的关键，以帮助确定治疗策略 靶向患者中的EMP-mROShigh表型。 阐明恶性淋巴细胞迁移和实体器官浸润的代谢基础， 为疾病生物学提供重要的见解，并发现淋巴结转移的新治疗策略。 由于与橙子剂有关，与退伍军人人群高度相关的恶性肿瘤（如CLL） 和其他除草剂暴露的风险。