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: 10558474
• 负责人: Neil A. Bhowmick
• 金额: $ 35.98万
• 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/10558474
• 关键词: Affect; Binding; Bioinformatics; Biometry; Bone Morphogenetic Proteins; 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：脂肪在肝脏转移性植入和扩张中的作用 摘要 实体瘤向肝脏的转移可能是由于获得了能够在肿瘤内存活的特征。 支持性转移小生境。我们发现肝脏龛一般不利于前列腺的扩张 癌然而，用高脂肪饮食喂养宿主小鼠两周足以使前列腺癌 在肝脏中生长。同样，胰腺癌和结肠癌细胞表现出更大的扩张，如果小鼠 高脂肪饮食和低脂饮食的对比。肝细胞和癌上皮细胞的暴露 细胞的饱和脂肪酸，棕榈酸，被发现可以促进转化生长因子的表达， β/骨形态发生蛋白共受体、内皮糖蛋白以及它们的配体。我们发现前列腺癌 CD 36（一种促转移脂肪酸受体）的上皮表达依赖于内皮糖蛋白信号传导， 循环脂肪的背景。基于这些新的发现，我们测试了中和内皮糖蛋白信号是否影响肝脏 转移，并发现肝细胞和癌上皮细胞中的差异内皮糖蛋白信号传导可以 协同促进肝转移。我们假设，循环脂肪可以转换，否则 转移抑制肝脏微环境是肿瘤允许的，并且它可以促进上皮细胞 以内皮素依赖的方式在肝脏中存活。在目标1中，我们将定义内皮素相关的变化， 使转移性移植成为可能。我们将系统地确定脂肪如何影响内皮素介导的 肝细胞谷氨酰胺合成酶的表达及其对肝星状细胞活化的影响 前列腺癌胰腺癌和结肠癌的肝脏移植在目标2中，我们将确定循环脂肪对 肿瘤上皮细胞在肝移植方面的作用。我们将探讨内皮素-CD 36串扰的性质， 癌上皮细胞，以及它如何促进与癌相关的Yes相关蛋白（雅普）信号传导轴。 FOXM 1下游的转移使能特性。在目标3中，我们将确定脂肪酸的作用 肿瘤上皮细胞在肝脏小生境内的扩张。我们将研究肝脏生态系统与信号 肝细胞和癌上皮细胞中的脂肪持续存在相互作用。我们发现脂肪诱导谷氨酰胺 由肝细胞以内皮素依赖性方式合成。肝细胞源性 将阐明谷氨酰胺诱导肝星状细胞活化和癌上皮分化。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癌细胞 以及那些扩散到肝脏的。