(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

基本信息

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
项目类别：
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&apos s lymphoma metabolomics molecular subtypes network architecture novel novel therapeutics programs response small molecule support network tumor tumor growth tumorigenesis

项目摘要

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.

项目概要线粒体网络由融合和裂变动力学形成，最终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) 代谢回路的剖析确定了具有不同特征的 DLBCL 亚型线粒体结构和生化网络的异质性燃料利用模式。 OxPhos-DLBCL 显示线粒体碎片净增加，并依赖于线粒体脂肪酸氧化 (FAO) 促进生存和增殖，不依赖于 B 细胞受体 (BCR) 发信号。这与非 OxPhos/Warburg 型 DLBCL 不同，非 OxPhos/Warburg 型 DLBCL 依赖于 BCR，依赖于糖酵解并有连接的线粒体网络。重要的是，阻断 OxPhos-DLBCL 中的碎片可以减少线粒体 FA 利用能力，但不改变其他燃料的消耗。上述观察结果表明，在促进线粒体处理中对片段化的特定要求 FA，并将线粒体形态异质性与 DLBCL 的燃料选择和代谢专业化联系起来亚型。为了回应 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。在目标 1 中，我们将定义机制 OxPhos- 与 BCR-DLBCL 中线粒体碎片净增加的决定因素，包括变化单个线粒体水平的融合和裂变率以及线粒体塑造蛋白的改变。我们还将解决线粒体碎片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，我们将了解线粒体的后果总体而言，燃料利用的碎片化，特别是粮农组织的燃料利用的碎片化。碳追踪和将进行生化研究以确定线粒体 FA 调节的机制通过 OxPhos-DLBCL 中的线粒体碎片进行处理。在目标 3 中，我们将确定线粒体如何结构和燃料代谢由 BCR 发起的信号调节，并探讨这些信号的相关性 BCR-DLBCL 对临床相关 BCR 抑制剂敏感性的线粒体途径。总之，这些研究可以提供重要的概念进步和机制见解 DLBCL 中线粒体形态的特化与支持肿瘤生长的燃料利用交织在一起。