Metabolic Reprogramming of Colon Cancer Liver Metastasis

结肠癌肝转移的代谢重编程

• 批准号: 9205492
• 负责人: Jason W. Locasale
• 金额: $ 17.29万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-13 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9205492
• 关键词: Animal Model; Cancer Etiology; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; Collection; Colon; Colon Carcinoma; Colorectal Cancer; Computer software; Custom; DNA Sequence Alteration; Data; Diet; Disseminated Malignant Neoplasm; Distant; Distant Metastasis; Drops; Enzyme Inhibition; Enzymes; Experimental Models; Growth; Human; Liver; Liver neoplasms; Location; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic; Metabolic Pathway; Metabolism; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Metastatic to; Modeling; Neoplasm Metastasis; Organ; Pathway Analysis; Pathway interactions; Patients; Phenotype; Primary Neoplasm; Resolution; Sampling; Site; Source; Survival Rate; System; Systems Analysis; Testing; United States; animal data; base; biobank; cancer cell; cancer subtypes; cancer type; chemotherapy; colon cancer patients; colon growth; data modeling; in vivo; in vivo Model; liquid chromatography mass spectrometry; metabolome; metabolomics; metastatic colorectal; mortality; mouse model; neoplastic cell; oncology; patient population; public health relevance; small hairpin RNA; small molecule inhibitor; transcriptome; transcriptome sequencing; transcriptomics; tumor; tumor growth

 DESCRIPTION (provided by applicant): Metastasis of cancer cells from the primary site to distant organs is a major cause of cancer-related death, as current chemotherapies are largely ineffective against metastasis. Recent data from the PIs' lab suggest that colorectal cancer (CRC) cells may undergo remarkable metabolic reprogramming after they metastasize to liver, which is the most common site for CRC metastasis. This discovery makes the conceptual argument that altered metabolism may contribute to metastatic phenotypes. The proposed study will use an integrative systems approach to understand metabolic reprogramming of CRC liver metastasis. Primary and liver tumors from an in vivo CRC metastasis model will be profiled by RNA-seq and high-resolution, liquid chromatography-mass spectrometry (LC-MS) based metabolomics. Integrated network analysis of the transcriptome and metabolome will identify altered metabolic pathways in CRC metastases. The findings will be corroborated by an extensive clinical biobank that contains a large collection of CRC liver metastases. Based on the integrative systems analysis, this study will then explore the hypothesis that manipulation of metabolic reprogramming will interfere with growth of CRC liver metastasis. Preliminary data suggest that targeting dysregulated metabolism, which includes inhibition of enzymes and restrictive diets, can interfere with growth of liver metastases more than frontline chemotherapy can in animal models. Since metastatic tumor cells have to adapt to their new microenvironment, targeting metabolic reprogramming of metastasis may be a viable approach for multiple cancer types and a significant percentage of the patient population.