Metabolic adaptation in lymphoid malignancies

淋巴恶性肿瘤的代谢适应

• 批准号: 10305636
• 负责人: Ji Zhang
• 金额: $ 42.84万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10305636
• 关键词: Acute Lymphocytic Leukemia; Affect; Amino Acids; Anabolism; Asparagine; Aspartate; Aspartate-Ammonia Ligase; B-Cell Lymphomas; Biochemical Genetics; Biological Availability; Bypass; Cancer Patient; Catabolism; Cell Proliferation; Cellular Metabolic Process; Childhood Acute Lymphocytic Leukemia; Chromatin; Citric Acid Cycle; Clinic; Complex; Consumption; DNA; Data; Dependence; Development; Environment; Enzymes; Face; Gene Expression; Genes; Genetic Transcription; Glutamine; Goals; Leukemic Cell; MYC Family Protein; Malignant Neoplasms; Malignant lymphoid neoplasm; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Methylation; Modeling; Molecular; Neoplastic Lymphocyte; Non-Essential Amino Acid; Nutrient; Oncogenic; Pathway interactions; Patients; Play; Process; Production; Promoter Regions; Protein Biosynthesis; Proto-Oncogenes; Refractory; Resistance; Role; Signal Transduction; Therapeutic; Therapeutic Intervention; Tissues; Translating; Translations; Variant; Vascular blood supply; acute lymphoblastic leukemia cell; asparaginase; biological adaptation to stress; cancer cell; cancer therapy; cell growth; deprivation; dietary restriction; genetic approach; improved; in vivo; macromolecule; mouse model; neoplastic cell; new therapeutic target; programs; promoter; response; therapy resistant; transamination; transcription factor; translational approach; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT Transformation-associated changes in regulating cell growth and proliferation result in specific nutrient or metabolic enzyme dependencies that are absent in non-transformed cells. Thus, nutrient dependency has recently been shown to be therapeutically exploitable in cancer. On the other hand, cancer cells frequently face nutrient limitation resulting from environmental variations, such as poor vascular supply, enhanced local consumption, dietary restriction and response to therapeutics. As a result, cancer cells become increasingly dependent on adaptive responses to mitigate metabolic stress. Therefore, defining the metabolites and the stress response pathways on which cancer cells depend will facilitate development of better therapeutic strategies that can improve management of cancer patients. For example, glutamine, a versatile biosynthetic substrate in cancer cells, is frequently found depleted in tumor environment when compared to normal surrounding tissues. We recently demonstrated that asparagine, a nonessential amino acid, plays a critical role in regulating tumor cells' adaptation to glutamine depletion, raising the potential to target asparagine bioavailability to treat cancer. However, little is known about how tumor cells sense and respond to asparagine deficiency. In this proposal, we will use lymphoid malignancies as models to explore the role of adaptive amino acid response in tumor cells' response to asparagine availability and its implication in cancer therapy. Our central hypothesis is that: neoplastic lymphocytes rely on de novo biosynthesis to produce asparagine when environmental asparagine becomes limiting. This adaptive program requires both the expression of key biosynthetic enzyme and the availability of glutamine-derived biosynthetic substrates, which can collectively affect oncogenic signaling beyond their roles in biosynthesis. Using biochemical, genetic and translational approaches, we will: (1) determine signaling and chromatin-modifying components regulating cellular adaptation to asparagine deprivation in acute lymphoblastic leukemia (ALL) and (2) determine impact of glutamine/asparagine metabolism on oncogenic MYC function in ALL and MYC-driven B cell lymphoma.

项目概要/摘要 调节细胞生长和增殖的转化相关变化导致特定的营养或 非转化细胞中不存在代谢酶依赖性。因此，营养依赖性 最近被证明可用于治疗癌症。另一方面，癌细胞经常面临 由于环境变化造成的营养限制，例如血管供应不良、局部营养增强 消费、饮食限制和对治疗的反应。结果，癌细胞变得越来越多 依赖于适应性反应来减轻代谢压力。因此，定义代谢物和应激 癌细胞所依赖的反应途径将有助于开发更好的治疗策略 可以改善癌症患者的管理。例如，谷氨酰胺，一种多功能生物合成底物 与周围正常组织相比，肿瘤细胞经常被发现在肿瘤环境中被耗尽。 我们最近证明天冬酰胺是一种非必需氨基酸，在调节肿瘤方面发挥着关键作用 细胞对谷氨酰胺消耗的适应，提高了靶向天冬酰胺生物利用度来治疗癌症的潜力。 然而，人们对肿瘤细胞如何感知和响应天冬酰胺缺乏知之甚少。在这个提案中，我们 将使用淋巴恶性肿瘤作为模型来探索适应性氨基酸反应在肿瘤细胞中的作用 对天冬酰胺可用性的反应及其在癌症治疗中的意义。我们的中心假设是：肿瘤性 当环境天冬酰胺变得不稳定时，淋巴细胞依靠从头生物合成来产生天冬酰胺。 限制。这种适应性程序既需要关键生物合成酶的表达，又需要 谷氨酰胺衍生的生物合成底物，它们可以共同影响致癌信号传导超出其作用 在生物合成中。使用生化、遗传和翻译方法，我们将：（1）确定信号传导和 染色质修饰成分调节细胞对急性淋巴细胞缺乏天冬酰胺的适应 白血病 (ALL) 和 (2) 确定谷氨酰胺/天冬酰胺代谢对致癌 MYC 功能的影响 ALL 和 MYC 驱动的 B 细胞淋巴瘤。