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.

项目摘要/摘要 肺癌是与癌症相关死亡的主要原因。肺腺癌（LUAD）是最大的 经常类型。 LUAD的发病机理知之甚少。我们最近发现钠葡萄糖 转运蛋白2（SGLT2）是以前未认可的代谢供应系统 LUAD阶段，肺癌发生所需。 SGLT2抑制延长生存，延迟癌症 发育，并减慢基因工程鼠模型（GEMM）和患者的肿瘤生长 LUAD的衍生异种移植物（PDX）。恶性病变和早期LUADS表达SGLT2，但不能 众所周知的Glut1转运蛋白，而更高级肿瘤显示SGLT2的异质表达 在同一肿瘤的高级区域中的低级和GLUT1中。为什么肿瘤需要从SGLT2切换到 glut1随着他们的进展吗？我们的数据表明，此开关与葡萄糖的重编程有关 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Gluts而非SGLT和甲基4- [18F]氟脱氧葡萄糖（ME4FDG）运输，特异于SGLT。 我们将研究LUAD葡萄糖转运的异质性，以了解生物学 显着性和调节SGLT2和GLUT1表达的机制。在AIM 1中，我们将 表征ME4FDG+中的葡萄糖代谢与fdg+ gemms中的FDG+肿瘤以及PET成像中的PDX中的肿瘤， 有或没有CRISPR SGLT2和GLUT1的敲除或过表达。在AIM 2中，我们将研究GSK3激酶的作用， 我们确定为SGLT2调节剂，在与与 从SGLT2切换到GLUT1。在AIM 3中，我们将研究缺氧在从SGLT2转换为 luad从良好的分化到差异很差，包括FDG之间的相关性，GLUT1表达 或ME4FDG吸收缺氧标记（F-Miso，pimonidazole），并评估缺氧的作用 SGLT和GLUT依赖性摄取的诱导因子敲除。 拟议研究的目的是阐明一种新型的代谢重编程机制 在癌症中：在两个不同的葡萄糖转运蛋白之间切换，癌细胞可以重定向 葡萄糖朝着不同的途径；这种观察具有重要的含义，因为干扰了沃堡 已经提出了作用或葡萄糖转运作为癌症的新疗法。癌细胞的能力 通过切换葡萄糖转运蛋白来改变其新陈代谢是一种潜在的抗药性机制， 因为有特定的sglt2和Glut抑制剂。而且，可以的宠物示踪剂可以 在体内有选择性地测量SGLT或GLUT活动（分别为ME4FDG和FDG）是一个有前途的工具 为了预测其对治疗的反应，表征癌症的代谢表型。