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：脂肪在肝脏转移性移植和扩张中的作用