Metabolic Reprogramming of Colon Cancer Liver Metastasis

 描述(申请人提供)：癌细胞从原发部位转移到远处器官是癌症相关死亡的主要原因，因为目前的化疗大多对转移无效。来自PIS实验室的最新数据表明，结直肠癌(CRC)细胞在转移到肝脏后可能经历显著的代谢重新编程，肝脏是CRC最常见的转移部位。这一发现提出了一个概念性的论点，即新陈代谢的改变可能会导致转移表型。 这项拟议的研究将使用综合系统方法来了解结直肠癌肝转移的代谢重新编程。来自体内CRC转移模型的原发肿瘤和肝脏肿瘤将通过RNA-SEQ和基于高分辨率的LC-MS(LC-MS)代谢组学来描述。转录组和代谢组的综合网络分析将确定结直肠癌转移过程中代谢途径的改变。这一发现将得到一个广泛的临床生物库的证实，该库包含大量的CRC肝转移瘤。 在综合系统分析的基础上，本研究将探索代谢重编程操作将干扰结直肠癌肝转移生长的假说。初步数据表明，靶向代谢失调，包括抑制酶和限制饮食，在动物模型中对肝转移瘤生长的干扰程度比一线化疗更大。由于转移的肿瘤细胞必须适应其新的微环境，靶向代谢重编程转移可能是一种可行的方法，对于多种癌症类型和相当大比例的患者群体。

 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.