Project 1- Role of fat in metastatic engraftment and expansion in the liver

项目 1 - 脂肪在肝脏转移植入和扩张中的作用

• 批准号: 10807146
• 负责人: Neil A. Bhowmick
• 金额: $ 14.09万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-21 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10807146
• 关键词: Affect; Binding; Bioinformatics; Biometry; Bone Morphogenetic Proteins; Butyrates; CD36 gene; Carcinoma; Cell Surface Receptors; Cell Survival; Cells; Cessation of life; Collaborations; Colon Carcinoma; ENG gene; Ecosystem; Endoglin; Energy-Generating Resources; Engraftment; Epithelial Cells; Epithelium; Exposure to; FOXM1 gene; FRAP1 gene; Fat-Restricted Diet; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Glutamate-Ammonia Ligase; Glutamine; Growth; Hepatic Stellate Cell; Hepatocyte; High Fat Diet; Incidence; Intake; Ligands; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Liver; Mus; Nature; Neoplasm Circulating Cells; Neoplasm Metastasis; Neutralization Tests; Palmitates; Pathway interactions; Play; Primary Neoplasm; Property; Regulation; Resistance; Resources; Role; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Signaling Protein; Site; Solid Neoplasm; Testing; Time; Transforming Growth Factor beta; Tumor Expansion; bone; cancer cell; cancer type; circulating cancer cell; colon cancer metastasis; curative treatments; fatty acid oxidation; feeding; lymph nodes; mortality; neoplastic cell; notch protein; novel; paracrine; patient population; permissiveness; prostate cancer metastasis; receptor; response; saturated fat; stem; synergism; therapeutic target; tumor; tumorigenesis; tumorigenic; uptake

PROJECT 1: Role of fat in metastatic engraftment and expansion in the liver ABSTRACT The metastasis of solid tumors to the liver may be a result of acquisition of features that enable survival within a supportive metastatic niche. We found that the liver niche is generally not conducive to the expansion of prostate cancer. However, feeding host mice with a high-fat diet for two weeks was sufficient to enable prostate cancer growth in the liver. Similarly, pancreatic and colon cancer cells demonstrated greater expansion if the mice were fed a high-fat diet versus if they were given a low-fat diet. The exposure of hepatocytes and cancer epithelial cells to a saturated fatty acid, palmitate, was found to promote the expression of transforming growth factor- β/bone morphogenic protein co-receptor, endoglin, as well as their ligands. We found that prostate cancer epithelial expression of CD36, a pro-metastatic fatty acid receptor, is dependent on endoglin signaling in the context of circulating fat. Based on these novel findings, we tested if neutralizing endoglin signaling affected liver metastasis, and found that differential endoglin signaling in hepatocytes and cancer epithelial cells could cooperatively contribute to liver metastasis. We hypothesize that circulating fat can convert the otherwise metastasis-inhibitory liver microenvironment to be tumor-permissive, and that it can promote epithelial cell survival in the liver in an endoglin-dependent manner. In Aim 1, we will define endoglin-associated changes in the liver that enable metastatic engraftment. We will systematically determine how fat affects endoglin-mediated expression of glutamine synthetase by hepatocytes and its effects on hepatic stellate cell activation in support of prostate, pancreatic, and colon cancer liver engraftment. In Aim 2, we will identify the role of circulating fat on tumor epithelial cells with regard to liver engraftment. We will explore the nature of endoglin-CD36 crosstalk in cancer epithelial cells, and how it promotes the Yes-associated protein (YAP) signaling axis associated with metastasis-enabling properties downstream of FOXM1. In Aim 3, we will identify the role that fatty acids have on the expansion of tumor epithelial cells within the liver niche. We will study the liver ecosystem with signaling interactions perpetuated by fat in hepatocytes and cancer epithelial cells. We identified that fat induces glutamine synthesis by hepatocytes in an endoglin-dependent manner. The mechanism by which hepatocyte-derived glutamine induces hepatic stellate cell activation and cancer epithelial differentiation will be elucidated. We will test a reciprocal relationship between the liver and tumor epithelial cells, as fat impacts circulating cancer cells and those disseminated to the liver.

项目1：脂肪在转移植入和肝脏扩张中的作用 抽象的 实体瘤向肝脏的转移可能是获得能够在A内生存的特征的结果 支持性转移性利基。我们发现，肝脏利基通常不用于前列腺膨胀 癌症。但是，用高脂饮食喂养宿主小鼠两周足以使前列腺癌 肝脏的生长。同样，如果小鼠为 如果给予低脂饮食，则喂养高脂饮食。肝细胞和癌症上皮的暴露 发现细胞到饱和脂肪酸，棕榈酸酯，可促进转化生长因子的表达 β/骨形态形态蛋白共受体，内生及其配体。我们发现前列腺癌 CD36的上皮表达是一种促脂肪酸接收器，取决于内ognignertign 循环脂肪的背景。基于这些新发现，我们测试了中和内og信号是否影响肝脏 转移，发现肝细胞和癌症上皮细胞中的差异内源信号传导可以 合作有助于肝转移。我们假设循环脂肪可以转换为否则 抑制转移的肝微环境是肿瘤的，并且可以促进上皮细胞 以依赖于内聚物的方式在肝脏中的生存。在AIM 1中，我们将定义与内聚物相关的变化 使转移性植入的肝脏。我们将系统地确定脂肪如何影响内og介导的 通过肝细胞表达谷氨酰胺合成酶及其对肝星状细胞激活的影响 前列腺，胰腺和结肠癌肝脏的参与。在AIM 2中，我们将确定循环脂肪在 肿瘤上皮细胞在肝脏植入方面。我们将在 癌症上皮细胞及其如何促进与是相关的蛋白（YAP）信号轴 FOXM1下游的增生特性。在AIM 3中，我们将确定脂肪酸具有的作用 关于肝细分市场中肿瘤上皮细胞的扩张。我们将通过信号研究肝脏生态系统 在肝细胞和癌症上皮细胞中脂肪永存的相互作用。我们确定脂肪会诱导谷氨酰胺 以肝细胞为依赖于肝细胞的合成方式。肝细胞衍生的机制 谷氨酰胺诱导星状细胞激活，癌症上皮分化将被阐明。我们将 测试肝脏和肿瘤上皮细胞之间的相互关系，因为脂肪会影响循环的癌细胞 那些传播到肝脏。