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: 9885813
• 负责人: Claudio Scafoglio
• 金额: $ 52.38万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9885813
• 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; Expression Profiling; Genetically Engineered Mouse; Glucose; Glucose Transporter; Glutamine; Glycolysis; Goals; Growth; HIF1A gene; Heterogeneity; Histology; Hypoxia; Hypoxia Inducible Factor; Immunohistochemistry; In Vitro; Insulin; Knock-out; Knockout Mice; 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; Pharmacology; Phenotype; Phosphotransferases; Pimonidazole; Play; Population; Positron-Emission Tomography; Proto-Oncogene Proteins c-akt; Regulation; Research; Resistance development; Role; SLC2A1 gene; Sodium; System; TP53 gene; Testing; Tracer; Transgenic Organisms; Tumor stage; Warburg Effect; Xenograft procedure; aerobic glycolysis; cancer cell; cancer therapy; fluorodeoxyglucose; glucose metabolism; glucose transport; glucose uptake; improved; in vivo; inhibitor/antagonist; lung carcinogenesis; lung xenograft; metabolic phenotype; metabolomics; mitochondrial membrane; mitochondrial metabolism; new therapeutic target; novel; novel therapeutics; overexpression; premalignant; programs; resistance mechanism; therapy resistant; tool; transcriptomics; treatment response; tumor; tumor growth; 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.

项目摘要/摘要 肺癌是癌症相关死亡的主要原因；肺腺癌(LUAD)是最主要的 常见型。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，特别活跃在早期- LUAD期，肺癌发生所需。抑制SGLT2延长生存期，延缓癌症 在基因工程小鼠模型(GEMM)和患者中，肿瘤生长缓慢。 LUAD来源异种移植(PDX)。癌前病变和早期LUAD表达SGLT2，但不表达 已知的GLUT1转运体，而更晚期的肿瘤表现出SGLT2的异质性表达 在同一肿瘤的低级别和高级别区域中GLUT1。为什么肿瘤需要从SGLT2切换到 随着他们的进步，Glut1？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 体内摄取可通过2-[18F]氟代脱氧葡萄糖(FDG)的正电子发射断层扫描(PET)进行研究， 由谷氨酸而不是SGLT运输，以及SGLT特有的甲基4-[18F]氟代脱氧葡萄糖(Me4FDG)。 我们将研究LUAD中葡萄糖转运的异质性，以了解 SGLT2和GLUT1表达的调控机制及意义在目标1中，我们将 用正电子发射计算机断层扫描研究GEMM和PDX中Me4FDG+和FDG+肿瘤的葡萄糖代谢， 呼吸计量学、代谢组学、代谢跟踪、组织学和转录学，有或没有CRISPR SGLT2和GLUT1基因被敲除或过表达。在目标2中，我们将研究GSK3激酶的作用，它 我们鉴定为SGLT2调节因子，参与调节代谢/分化程序 从SGLT2切换到GLUT1。在目标3中，我们将研究低氧在SGLT2到SGLT2转换中的作用 LUAD从高分化到低分化过程中Glut1的表达，包括FDG之间的相关性 或Me4FDG摄取与低氧标志物(F-MISO，匹莫硝唑)，并评估低氧的影响- SGLT和过量依赖摄取的诱导因子敲除。 这项拟议研究的目标是阐明一种新的代谢重编程机制 在癌症中：在两种不同的葡萄糖转运体之间切换，癌细胞可以改变其代谢命运 葡萄糖走向不同的途径；这一观察结果具有重要的意义，因为它干扰了Warburg 通过葡萄糖转运的作用已被提出为癌症的一种新疗法；癌细胞 通过切换葡萄糖转运蛋白来改变它们的代谢是一种潜在的靶向抗药性机制， 因为SGLT2和Glut都有特异性的抑制剂。此外，PET示踪剂的可用性可以 选择性地测量体内SGLT或GLUT活性(分别为Me4FDG和FDG)是一种很有前途的工具 表征体内癌症的代谢表型，以预测其对治疗的反应。