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 实体瘤转移到肝脏可能是由于获得了能够在体内存活的特征 支持性转移的利基。我们发现肝龛一般不利于前列腺的扩张。 癌症。然而，用高脂肪饮食喂养宿主小鼠两周就足以导致前列腺癌 肝脏中的生长。同样，胰腺和结肠癌细胞表现出更大的扩张性，如果小鼠 给他们喂高脂肪饮食与给他们低脂肪饮食。肝细胞与癌上皮细胞的暴露 细胞对一种饱和脂肪酸棕榈酸酯的转化生长因子的表达有促进作用。 β/骨形态发生蛋白共受体Endoglin及其配体。我们发现前列腺癌 CD36是一种促进肿瘤转移的脂肪酸受体，其上皮细胞的表达依赖于Enoglin信号。 循环脂肪的背景。基于这些新的发现，我们测试了中和endoglin信号是否会影响肝脏 转移，并发现肝细胞和癌细胞中不同的endoglin信号可以 协作性地促进肝脏转移。我们假设循环中的脂肪可以转化为 抑制转移的肝脏微环境具有肿瘤容许性，并能促进上皮细胞 在肝脏中以内源性依赖的方式存活。在目标1中，我们将定义与endoglin相关的更改 使转移性植入成为可能的肝脏。我们将系统地确定脂肪如何影响endoglin介导的 谷氨酰胺合成酶在肝细胞中的表达及其对肝星状细胞激活的影响 前列腺癌、胰腺癌和结肠癌的肝移植。在目标2中，我们将确定循环脂肪在 肿瘤上皮细胞与肝移植的关系。我们将探索endoglin-CD36串扰的本质 癌上皮细胞及其如何促进YAP信号轴与 FOXM1下游的转移使能特性。在目标3中，我们将确定脂肪酸所起的作用 肿瘤上皮细胞在肝龛内的扩张。我们将研究肝脏生态系统中的信号 脂肪在肝细胞和癌细胞中的相互作用。我们发现脂肪可以诱导谷氨酰胺 肝细胞以内源性激素依赖的方式合成。肝细胞来源的机制 谷氨酰胺诱导肝星状细胞活化和癌上皮分化将被阐明。我们会 测试肝脏和肿瘤上皮细胞之间的相互关系，因为脂肪影响循环中的癌细胞 和那些扩散到肝脏的。