Image-Based Phenotyping of Hepatocellular Carcinoma Cell Survival Under Ischemic Stress: Toward Metabolic Imaging of Cancer Dormancy Using Hyperpolarized Carbon-13 Technology

基于图像的缺血应激下肝细胞癌细胞存活表型：使用超极化碳 13 技术实现癌症休眠的代谢成像

• 批准号: 9150682
• 负责人: Terence P Gade
• 金额: $ 40万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9150682
• 关键词: 2,4-Dinitrophenol; Acetates; Acids; Animal Model; Apoptosis; Arterial Embolization; Autophagocytosis; Biological Models; Biology; Blood Vessels; Cancer Survivor; Carbamyl Phosphate; Carbohydrates; Carbon; Carbon Dioxide; Cell Survival; Cells; Chemoembolization; Clinical; Dependence; Detection; Development; Disease; Environment; Enzymes; Epigenetic Process; Extensive Necrosis; Fingerprint; Fructose; Fumarates; Glucose; Glutamates; Glutamine; Growth; Guidelines; Health; Histology; Histopathology; Hypoxia Inducible Factor; Image; Imaging Techniques; Imaging technology; In Vitro; Ischemia; Label; Lesion; Leucine; Ligase; Lipids; Malates; Malignant Epithelial Cell; Malignant Neoplasms; Measurable; Measures; Metabolic; Metabolic stress; Metabolism; Modeling; NMR Spectroscopy; Necrosis; Non-Invasive Cancer Detection; Nuclear; Nutrient; Palmitates; Pathology; Patients; Phenotype; Primary carcinoma of the liver cells; Proliferating; Protein Biosynthesis; Proteins; Proteomics; Pyruvate; Rattus; Recurrence; Resources; Signal Transduction; Solid Neoplasm; Stress; Technology; Therapeutic; Therapeutic Embolization; Time; Tissues; Translating; Translations; Tumor Cell Necrosis; Work; alpha ketoglutarate; base; biological adaptation to stress; cancer cell; cancer imaging; carbohydrate metabolism; epigenetic profiling; follow-up; in vivo; indexing; lens; lipid biosynthesis; lipid metabolism; liver transplantation; metabolic abnormality assessment; metabolomics; neoplastic cell; novel; nutrient deprivation; pre-clinical; programs; protein metabolism; research study; response; spectroscopic imaging; targeted delivery; tumor; tumor metabolism

 DESCRIPTION (provided by applicant): Established guidelines for assessing response of solid tumors to therapy are based on conventional imaging indices, such as tumor size and vascularity, and were intended to facilitate a uniform assessment of response to systemically administered chemotherapeutics that target proliferating cells in a well-perfused microenvironment. An emerging imaging phenotype of tumor recurrence indicates that a complete radiographic response may be followed by variable periods of latency without perceptible growth in poorly perfused microenvironments. This imaging phenotype highlights the capability of cancer cells to adapt their growth program to their microenvironment and effect tumor dormancy. The development of functional measures of this altered tumor metabolism is critical to effective preclinical and clinical imaging of response. Trans-arterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma (HCC) provides a compelling clinical correlate to this imaging deficiency. TACE exploits the vascular biology of HCC to deprive tumors of nutrients, leading to necrosis; however, only 44% of large treated lesions demonstrate extensive necrosis on pathology, underscoring the adaptive response of HCC cells to nutrient deprivation. This adaptive response is reflected by the presence of viable tumor cells adjacent to regions of necrosis on histopathology, and is consistent with the rapid recurrence following a period of latency that is often discovered on follow-up imaging. Thus, TACE provides a useful model for identifying the mechanisms mobilized by cancer cells to survive severe ischemia. In preliminary studies, we have demonstrated that TACE-like severe ischemia induces quiescence in surviving cells and that these cells activate a metabolic stress response (MSR) including hypoxia-inducible factors, the unfolded protein response and autophagy, which reprogram metabolism to enable survival under ischemic conditions. The recent development of Dynamic Hyperpolarized Carbon-13 Nuclear Magnetic Resonance spectroscopy and spectroscopic imaging (DNP-13C-NMRS) has yielded promising results in studies of metabolism in hepatocellular disease. This technology represents a unique resource to translate advances in our understanding of the MSR into a non-invasive, clinically applicable imaging paradigm to identify dormant cancer cells surviving ischemia. The conventional post-TACE imaging phenotype of sustained survival without proliferation under metabolic stress will be examined using targeted metabolomics, proteomic and epigenetic profiling of HCC cells to develop a DNP-13C-NMRS based imaging approach. The primary objectives of this application are to: a) characterize the nutrient microenvironment as well as the epigenetic and proteomic alterations underlying MSR-induced metabolic adaptation in cells surviving ischemic stress, b) develop a DNP- 13C-NMRS based metabolic imaging approach to enable the non-invasive detection of cells surviving ischemic stress in vitro, and c) translate this approach to characterize cells surviving trans-arterial embolization in vivo.

 描述（由申请人提供）：评估实体瘤对治疗反应的既定指南基于常规成像指标，例如肿瘤大小和血管分布，旨在促进对靶向增殖细胞的全身化疗药物的反应进行统一评估。灌注良好的微环境中出现的肿瘤复发的成像表型表明，在灌注不良的微环境中，完整的放射照相反应可能会出现不同的潜伏期，而不会出现明显的生长。细胞使其生长程序适应其微环境并影响肿瘤休眠，这种改变的肿瘤代谢的功能测量的开发对于肝细胞癌（HCC）治疗的有效临床前和临床反应成像至关重要。 ）提供了与这种成像缺陷的令人信服的临床关联，TACE 利用 HCC 的血管生物学剥夺肿瘤的营养，导致坏死；然而，只有 44% 的大治疗病变表现出广泛的坏死。病理学上的坏死，强调了肝癌细胞对营养剥夺的适应性反应，这种适应性反应通过组织病理学上坏死区域附近存在存活的肿瘤细胞来反映，并且与通常经过一段潜伏期后的快速复发一致。因此，TACE 提供了一个有用的模型，用于识别癌细胞在严重缺血中存活的机制。在初步研究中，我们已经证明，类似 TACE 的严重缺血会诱导静止。存活细胞中，这些细胞激活代谢应激反应（MSR），包括缺氧诱导因子、未折叠蛋白反应和自噬，重新编程代谢以实现缺血条件下的生存。动态超极化碳 13 核磁共振的最新发展。光谱学和光谱成像 (DNP-13C-NMRS) 在肝细胞疾病代谢研究中取得了有希望的结果，这项技术代表了一种独特的资源，可以转化我们对疾病的理解的进展。将 MSR 转化为非侵入性、临床适用的成像范式，以识别在缺血中存活的休眠癌细胞。将使用 HCC 细胞的靶向代谢组学、蛋白质组学和表观遗传分析来检查在代谢应激下持续存活而不增殖的传统 TACE 后成像表型。开发基于 DNP-13C-NMRS 的成像方法，该应用的主要目标是：a) 表征营养微环境以及 MSR 诱导的细胞代谢适应的表观遗传和蛋白质组变化。 b) 开发基于 DNP- 13C-NMRS 的代谢成像方法，以实现体外非侵入性检测缺血应激中幸存的细胞，以及 c) 将此方法转化为表征体内经动脉栓塞中幸存的细胞。