Investigating the heterogeneity of glucose transport in lung adenocarcinoma

研究肺腺癌中葡萄糖转运的异质性

• 批准号: 10738343
• 负责人: Claudio Scafoglio
• 金额: $ 16.83万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10738343
• 关键词: Address; Agreement; Area; Biological; Cancer Etiology; Carcinoma; Cell Differentiation process; Cell Line; Cell Respiration; Cells; Cellular Metabolic Process; Cessation of life; Clustered Regularly Interspaced Short Palindromic Repeats; Coupled; Data; Development; Distal; Engineering; Evaluation; Genetically Engineered Mouse; Glucose; Glucose Transporter; Glutamine; Glycolysis; Goals; Growth; HIF1A gene; Heterogeneity; Histology; Hypoxia; Hypoxia Inducible Factor; Immunohistochemistry; In Vitro; Insulin; Knock-out; Lesion; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Mediating; Membrane Potentials; Metabolic; Metabolism; Mitochondria; Modality; Molecular; Morphology; Mus; Nodule; Pathogenesis; Pathway interactions; Patients; Phenotype; Phosphotransferases; Pimonidazole; Play; Population; Positron-Emission Tomography; Proto-Oncogene Proteins c-akt; Regulation; Research; Resistance development; Role; SLC2A1 gene; Sodium; Spirometry; System; TP53 gene; Testing; Tracer; Tumor stage; Warburg Effect; aerobic glycolysis; cancer cell; cancer therapy; constitutive expression; fluorodeoxyglucose; glucose metabolism; glucose transport; glucose uptake; glycogen synthase kinase 3 beta; improved; in vivo; inhibitor; lung carcinogenesis; metabolic phenotype; metabolomics; mitochondrial membrane; mitochondrial metabolism; new therapeutic target; novel; novel therapeutics; overexpression; patient derived xenograft model; pharmacologic; premalignant; progenitor; programs; resistance mechanism; therapy resistant; tool; transcriptomics; transgene expression; treatment response; tumor; tumor growth; tumor progression; uptake

Project Summary/Abstract Lung cancer is the leading cause of cancer-related death; lung adenocarcinoma (LUAD) is the most frequent type. The pathogenesis of LUAD is poorly understood. We recently discovered that sodium-glucose transporter 2 (SGLT2) is a previously unrecognized system of metabolic supply specifically active in early- stage LUAD and required for lung carcinogenesis. SGLT2 inhibition prolongs survival, delays cancer development, and slows tumor growth in genetically engineered murine models (GEMMs) and in patient- derived xenografts (PDXs) of LUAD. Pre-malignant lesions and early-stage LUADs express SGLT2 but not the well-known GLUT1 transporter, whereas more advanced tumors display heterogeneous expression of SGLT2 in low-grade and GLUT1 in high-grade areas of the same tumor. Why do tumors need to switch from SGLT2 to GLUT1 as they progress? Our data suggest that this switch is associated with a reprogramming of glucose metabolism: SGLT2+ tumors use oxidative glucose metabolism, GLUT1+ tumors use glycolysis. Glucose uptake can be studied in vivo by positron emission tomography (PET) with 2-[18F] fluorodeoxyglucose (FDG), transported by GLUTs and not SGLTs, and methyl 4-[18F]fluorodeoxyglucose (Me4FDG), specific for SGLTs. We will investigate the heterogeneity of glucose transport in LUAD, to understand the biological significance and the mechanisms that regulate the expression of SGLT2 and GLUT1. In Aim 1, we will characterize glucose metabolism in Me4FDG+ versus FDG+ tumors in GEMMs and in PDXs by PET imaging, respirometry, metabolomics, metabolic tracing, histology, and transcriptomics, with or without CRISPR knockout or overexpression of SGLT2 and GLUT1. In Aim 2, we will investigate the role of GSK3 kinase, which we identified as an SGLT2 regulator, in the regulation of metabolic/differentiation programs associated with the switch from SGLT2 to GLUT1. In Aim 3, we will investigate the role of hypoxia in the switch from SGLT2 to GLUT1 expression as LUAD progresses from well- to poorly differentiated, including correlation between FDG or Me4FDG uptake with markers of hypoxia (F-MISO, pimonidazole), and evaluation of the effect of hypoxia- inducible factors knockout on SGLT- and GLUT-dependent uptake. The goal of the proposed research is the elucidation of a novel mechanism of metabolic reprogramming in cancer: switching between two different glucose transporters, cancer cells can redirect the metabolic fate of glucose towards different pathways; this observation has important implications as interfering with the Warburg effect or with glucose transport has been proposed as a novel therapy for cancer; the ability of cancer cells to change their metabolism by switching glucose transporters is a potentially targetable mechanism of resistance, as there are specific inhibitors of both SGLT2 and GLUT. Moreover, the availability of PET tracers that can selectively measure SGLT or GLUT activity in vivo (Me4FDG and FDG, respectively) is a promising tool for characterizing the metabolic phenotype of cancers in vivo, in order to predict their response to treatments.

项目概要/摘要 肺癌是癌症相关死亡的主要原因；肺腺癌（LUAD）是最常见的 频繁型。 LUAD 的发病机制尚不清楚。我们最近发现葡萄糖钠 转运蛋白 2 (SGLT2) 是一种以前未被认识的代谢供应系统，特别活跃于早期 LUAD 阶段，是肺癌发生所必需的。 SGLT2 抑制可延长生存期、延缓癌症发生 发育，并减缓基因工程小鼠模型（GEMM）和患者体内的肿瘤生长 LUAD 的衍生异种移植物 (PDX)。癌前病变和早期 LUAD 表达 SGLT2，但不表达 众所周知的 GLUT1 转运蛋白，而更晚期的肿瘤则表现出 SGLT2 的异质表达 同一肿瘤的低级别区域中存在 GLUT1，高级别区域中存在 GLUT1。为什么肿瘤需要从 SGLT2 转换为 GLUT1 随着他们的进展？我们的数据表明这种转换与葡萄糖的重新编程有关 代谢：SGLT2+肿瘤使用​​氧化葡萄糖代谢，GLUT1+肿瘤使用​​糖酵解。葡萄糖 可以通过使用 2-[18F] 氟脱氧葡萄糖 (FDG) 的正电子发射断层扫描 (PET) 在体内研究摄取， 由 GLUT 而不是 SGLT 以及 SGLT 特有的甲基 4-[18F]氟脱氧葡萄糖 (Me4FDG) 运输。 我们将研究 LUAD 中葡萄糖转运的异质性，以了解其生物学意义 SGLT2 和 GLUT1 表达的意义和调节机制。在目标 1 中，我们将 通过 PET 成像表征 GEMM 和 PDX 中 Me4FDG+ 与 FDG+ 肿瘤的葡萄糖代谢特征， 呼吸测定法、代谢组学、代谢追踪、组织学和转录组学（使用或不使用 CRISPR） SGLT2 和 GLUT1 的敲除或过表达。在目标 2 中，我们将研究 GSK3 激酶的作用，它 我们确定其为 SGLT2 调节因子，可调节与 从 SGLT2 切换到 GLUT1。在目标 3 中，我们将研究缺氧在从 SGLT2 转换为 LUAD 从分化良好进展为分化较差时的 GLUT1 表达，包括 FDG 之间的相关性 或 Me4FDG 摄取与缺氧标志物（F-MISO、哌莫硝唑），以及缺氧效果的评估 SGLT 和 GLUT 依赖性吸收的诱导因子敲除。 拟议研究的目标是阐明代谢重编程的新机制 在癌症中：在两种不同的葡萄糖转运蛋白之间切换，癌细胞可以改变葡萄糖的代谢命运 葡萄糖流向不同的途径；这一观察结果对于干扰瓦尔堡具有重要意义 效应或葡萄糖转运已被提议作为癌症的新疗法；癌细胞的能力 通过切换葡萄糖转运蛋白来改变其代谢是一种潜在的可靶向耐药机制， 因为 SGLT2 和 GLUT 都有特定的抑制剂。此外，PET示踪剂的可用性可以 选择性测量体内 SGLT 或 GLUT 活性（分别为 Me4FDG 和 FDG）是一种很有前途的工具 表征癌症体内的代谢表型，以预测其对治疗的反应。