(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: 10239222
• 负责人: Nika N Danial
• 金额: $ 55.8万
• 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/10239222
• 关键词: Address; Architecture; B-Cell Antigen Receptor; 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; 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形成的，这些动力学最终会影响线粒体 利用燃料的能力。我们最近对弥漫性大B细胞淋巴瘤（DLBCL）代谢回路的解剖， 在DLBCL亚型中确定了线粒体结构和生化网络的异质性， 燃料利用模式。OxPhos-DLBCL显示线粒体片段化的净增加，并依赖于 线粒体脂肪酸氧化（FAO）用于生存和增殖，不依赖于B细胞受体（BCR） 信号这与非OxPhos/瓦尔堡型DLBCL不同，后者依赖于BCR，依赖于糖酵解 并连接了线粒体网络。重要的是，阻断OxPhos-DLBCL中的片段化减少了 线粒体FA利用能力，但不改变其他燃料的消耗。 上述观察结果表明，在促进线粒体处理细胞内蛋白质时， FAs，并将DLBCL中线粒体形态异质性与燃料选择和代谢特化联系起来 亚型为响应RFA-CA-17-017 PQ 5，拟定研究检查了机制， 这种联系的后果及其与肿瘤发生的相关性。在目标1中，我们将定义 OxPhos与BCR-DLBCL中线粒体碎片净增加的决定因素，包括 在单个线粒体水平上的融合和分裂速率以及线粒体形成蛋白质的改变。 我们还将探讨线粒体断裂改变对生长和存活的长期影响 DLBCL亚型的体外和体内研究。在目标2中，我们将了解线粒体 一般而言，燃料利用的分散性，特别是粮农组织的分散性。碳追踪和 将进行生化研究以确定线粒体FA调节的潜在机制 通过OxPhos-DLBCL中的线粒体片段化进行处理。在目标3中，我们将确定线粒体如何 结构和燃料代谢的调节BCR启动的信号，并探讨这些相关性 线粒体途径与BCR-DLBCL对临床相关BCR抑制剂的敏感性有关。 总之，这些研究可以提供重要的概念进步和机械的见解，如何 DLBCL中的线粒体形态特化与支持肿瘤生长的燃料利用交织在一起。