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: 10426229
• 负责人: Stefan M Schieke
• 金额: --
• 依托单位: U.S. DEPT/VETS AFFAIRS MEDICAL CENTER
• 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/10426229
• 关键词: Affect; Automobile Driving; Behavior; Biology; Cell Line; Cell Separation; Cells; Chemicals; Chronic Lymphocytic Leukemia; Citric Acid Cycle; Clinical; Disease; Disease Progression; Environment; Exposure to; Generations; Genes; Genetic; Glucose; HIF1A gene; 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; Nutrient availability; Organ; Organ Transplantation; Patients; 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; pharmacologic; 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.

尽管最近的治疗取得了进展，但仍无法治愈淋巴恶性肿瘤，例如非霍奇金淋巴瘤和 淋巴细胞白血病仍然是一个临床挑战。虽然对预后至关重要，但调节机制 恶性淋巴细胞的运输、迁移和实体器官浸润尚不完全清楚。代谢 灵活性在癌症进展过程中发挥着至关重要的作用，使癌细胞的代谢需求与 特定的组织环境。然而，在淋巴癌中，人们对代谢的影响知之甚少。 细胞迁移和疾病进展的编程。我们的初步研究表明，恶性 淋巴细胞迁移和实体器官浸润与细胞代谢偏好密切相关。我们 发现异种移植模型中 T 和 B 淋巴细胞迁移和器官浸润 通过分析 mROSlow 和 mROShigh 由线粒体活性氧 (mROS) 确定 州。这种创新策略使我们能够分离具有不同迁移潜力的细胞来剖析燃料 “增强迁移潜力”-mROShigh (EMP-mROShigh) 状态的偏好。我们将葡萄糖确定为 一种通过激活 mROS/HIF-1a 信号传导驱动迁移的重要燃料。初始 13C-葡萄糖示踪 研究表明迁移细胞中的葡萄糖代谢被重新编程。减少 TCA 中的丙酮酸氧化 循环和乳酸生成的增强通过 HIF-1a 信号传导促进迁移。这些结果支持 我们的假设是丙酮酸通量的分支点是控制恶性的关键“代谢决策点” 淋巴细胞迁移和器官浸润。我们预测丙酮酸通量的动态变化 线粒体氧化和转化为乳酸通过以下方式控制迁移和浸润潜力 mROS/HIF-1a 依赖性细胞迁移程序的转录调控。具体目标如下 将检验这个假设： 目标 1. 确立丙酮酸通量作为控制恶性淋巴细胞决策点的作用 迁移和渗透。我们将检验以下假设：TCA 循环之间丙酮酸代谢的转变 氧化和还原为乳酸是恶性淋巴细胞迁移和固体的关键检查点。 通过调节 mROS/HIF-1a 信号传导进行器官浸润。 目标 2. 确定代谢决定控制迁移行为的分子机制 观点。该目标将检验丙酮酸通量作为代谢决策点控制迁移的假设 通过 mROS/HIF1a 依赖性细胞迁移程序的转录调节。我们将表演 对 CLL 细胞进行 RNAseq 分析，然后进行功能分析，以确定翻译代谢的基因 重新编程为迁移潜力。 目标 3：剖析增强型迁移癌细胞的燃料偏好和代谢重编程 通过 CLL 患者的体内代谢追踪。我们将检验 EMP-mROShigh 细胞的假设 在 CLL 患者体内显示出与体外类似的重新编程的葡萄糖和 TCA 循环代谢 表型。患者将被注入 13C 标记的营养物质以确定丙酮酸通量和 TCA 循环燃料 CLL 细胞在其体内栖息地的“增强迁移潜力”对于帮助确定治疗策略至关重要 针对患者的 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将 提供对疾病生物学的重要见解并发现淋巴样疾病的新治疗策略 诸如 CLL 等恶性肿瘤，由于与橙剂有关，因此与退伍军人群体高度相关 以及服兵役期间接触其他除草剂。