(PQ5) Contribution of mitochondrial pathways to metabolic heterogeneity in molecular subtypes of Diffuse Large B Cell Lymphoma

(PQ5) 线粒体途径对弥漫性大 B 细胞淋巴瘤分子亚型代谢异质性的贡献

• 批准号: 9768987
• 负责人: Nika N Danial
• 金额: $ 54.13万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768987
• 关键词: Address; Architecture; B-Cell Lymphomas; Biochemical; Biochemical Genetics; Carbon; Cell physiology; Complement; Consumption; Coupled; Data; Development; Diabetes Mellitus; Dissection; Energy Metabolism; Equilibrium; Genetic study; Glycolysis; Growth; Heterogeneity; Human; In Vitro; Individual; Investigation; Label; Learning; Link; Lipids; Lymphoma; Malignant Neoplasms; Mass Spectrum Analysis; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Molecular; Morphology; Obesity; Outcome; Oxides; Pathway interactions; Pattern; Process; Protein Dynamics; Proteins; Receptor Inhibition; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Research; Role; Shapes; Signal Transduction; Testing; Tracer; Tumorigenicity; base; clinically relevant; fatty acid oxidation; genetic approach; high resolution imaging; in vivo; inhibitor/antagonist; insight; large cell Diffuse non-Hodgkin' s lymphoma; metabolomics; molecular subtypes; network architecture; novel; novel therapeutics; programs; response; small molecule; support network; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY The mitochondrial network is shaped by fusion and fission dynamics that ultimately influence the mitochondrial capacity to utilize fuels. Our recent dissection of metabolic circuits in diffuse large B-cell lymphoma (DLBCL) has identified heterogeneity of mitochondrial architecture and biochemical networks in DLBCL subtypes with distinct patterns of fuel utilization. OxPhos-DLBCLs show a net increase in mitochondrial fragmentation and rely on mitochondrial fatty acid oxidation (FAO) for survival and proliferation independent of B-cell receptor (BCR) signaling. This is distinct from non-OxPhos/Warburg type DLBCLs that are BCR-dependent, rely on glycolysis and have connected mitochondrial network. Importantly, blocking fragmentation in OxPhos-DLBCLs reduces mitochondrial FA utilization capacity but does not alter consumption of other fuels. The above observations indicate a specific requirement for fragmentation in facilitating mitochondrial handling of FAs, and link mitochondrial morphologic heterogeneity to fuel choice and metabolic specialization in DLBCL subtypes. In response to RFA-CA-17-017 PQ5, the proposed studies examine the mechanisms and consequences of this link and its relevance to tumorigenesis. In Aim 1, we will define the mechanistic determinants of the net increase in mitochondrial fragmentation in OxPhos- vs BCR-DLBCLs, including changes in fusion and fission rates at the level of individual mitochondria and alterations in mitochondria-shaping proteins. We will also address the long-term consequences of altered mitochondrial fragmentation in growth and survival of DLBCL subtypes in vitro and in vivo. In Aim 2, we will learn about the consequence of mitochondrial fragmentation for fuel utilization in general and FAO in particular. A combination of carbon tracing and biochemical studies will be undertaken to determine the mechanisms underlying regulation of mitochondrial FA handling by mitochondrial fragmentation in OxPhos-DLBCLs. In Aim 3, we will determine how mitochondrial architecture and fuel metabolism are modulated by BCR-initiated signals, and probe the relevance of these mitochondrial pathways to the sensitivity of BCR-DLBCLs to clinically-relevant BCR inhibitors. Together, these studies can provide important conceptual advancement and mechanistic insights into how the mitochondrial morphologic specializations in DLBCLs are intertwined with fuel utilization to support tumor growth.

项目摘要 线粒体网络是由融合和裂变动力学塑造的，最终影响线粒体 利用燃料的能力。我们最近在扩散的大B细胞淋巴瘤（DLBCL）中解剖代谢回路已有 DLBCL亚型中线粒体结构和生化网络的鉴定的异质性 燃料利用的模式。 oxphos-dlbcls显示线粒体碎片的净增加，并依靠 线粒体脂肪酸氧化（FAO），用于生存和增殖，独立于B细胞受体（BCR） 信号。这与依赖于BCR的非氧气/Warburg类型DLBCL不同，依赖于糖酵解 并已经连接了线粒体网络。重要的是，阻塞Oxphos-DLBCL中的碎片减少了 线粒体FA利用能力，但不会改变其他燃料的消耗。 上述观察结果表明在促进线粒体处理方面的分裂需要 FAS和Link线粒体形态异质性与DLBCL的燃料选择和代谢专业化 亚型。为了响应RFA-CA-17-017 PQ5，拟议的研究检查了机制和 这种联系的后果及其与肿瘤发生的相关性。在AIM 1中，我们将定义机械 在Oxphos-vs BCR-DLBCL中线粒体碎片的净增加的决定因素，包括变化 在单个线粒体水平的融合和裂变速率中，线粒体成形蛋白的改变。 我们还将解决线粒体碎片在生长和生存中改变的长期后果 DLBCL亚型的体外和体内。在AIM 2中，我们将了解线粒体的后果 尤其是燃料利用的碎片，尤其是粮农组织。碳跟踪和 将进行生化研究以确定线粒体FA调节的基础机制 在Oxphos-DLBCL中通过线粒体碎片处理。在AIM 3中，我们将确定线粒体如何 建筑和燃料代谢受BCR发起的信号调节，并探究这些信号的相关性 线粒体对BCR-DLBCLS对临床上相关的BCR抑制剂的敏感性的途径。 这些研究共同提供了重要的概念进步和机械见解 DLBCL中的线粒体形态学专长与燃料利用相互交织以支持肿瘤生长。