Mechanisms and therapeutic targets of cancer metastasis

癌症转移的机制和治疗靶点

基本信息

批准号：
10307085
负责人：
Gregory L Beatty
金额：
$ 36.43万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10307085
关键词：
Acute-Phase Proteins Address Agonist Amyloid Proteins Biology CD47 gene Cancer Model Cell Proliferation Cells Clinical Cytotoxic Chemotherapy Deposition Development Disease Elements Environment Equilibrium Extracellular Matrix Extracellular Matrix Proteins Genetic Goals Growth Hepatic Stellate Cell Hepatocyte Immunologics Interleukin-6 KPC model KRASG12D Kupffer Cells Liver Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mechanics Metabolic Metastatic Neoplasm to the Liver Modeling Molecular Morbidity - disease rate Mus Myelogenous Myeloid Cells Nature Neoplasm Circulating Cells Neoplasm Metastasis Neutrophil Infiltration Non-Malignant Outcome Pancreas Pliability Primary Neoplasm Process Property Risk Role STAT3 gene Serum Shapes Signal Pathway Signal Transduction Soil TNFRSF5 gene Testing Therapeutic Treatment Efficacy Tropism Variant Work cancer cell cancer site carcinogenesis chemotherapy clinically relevant design human disease improved macrophage mortality mouse model neoplastic cell novel novel strategies novel therapeutics pancreatic ductal adenocarcinoma model prevent standard of care therapeutic target therapy design/development tool tumor

项目摘要

Project Summary Metastasis is the primary cause of morbidity and mortality in cancer with little improvement in outcomes over the past decade. This is particularly evident in gastrointestinal cancers where metastasis to the liver is the most common site of cancer cell spread. We hypothesize that the spread and growth of cancer cells in the liver is dependent on formation of a reversible niche environment that is directed by hepatocytes, the chief functional cells of the liver. In support of this hypothesis, we have found that primary tumors release soluble factors that activate hepatocytes in the liver. This process begins during the earliest stages of cancer development. Activated hepatocytes respond by releasing acute phase reactants which orchestrate a niche environment in the liver that is underpinned by the recruitment of neutrophils and myeloid cells and the deposition of extracellular matrix proteins. This environment supports cancer cell seeding and colonization. In the absence of this pro-metastatic niche, disseminated cancer cells enter a state of cell dormancy in the liver. Although macrophages are a first- line of defense against metastasis to the liver, their biology is also altered during formation of the niche environment in the liver. Thus, our findings identify an intercellular network within the liver underpinned by hepatocytes that responds to cancer development by preparing the “soil” that supports cancer cell “seeding”. Our ultimate goal is to devise novel therapies that will resolve the pro-metastatic niche and redirect the liver environment from pro- to anti-metastatic for treating and preventing cancer metastasis. However, this will require an understanding of the signals by which hepatocytes direct formation of the niche and identification of strategies capable of reversing the pro-metastatic potential of the niche. Therefore, in Aim 1, we will define the downstream signals by which hepatocytes coordinate formation of a pro-metastatic niche in the liver. In Aim 2, we will identify strategies to shift the niche environment in the liver from pro- to anti-metastatic. In Aim 3, we will investigate the impact of hepatocytes on cancer cell dormancy in the liver and the efficacy of cytotoxic chemotherapy. Together, these complementary aims will inform the development of therapies designed to condition the liver for anti- metastatic potential as a strategy to prevent and treat cancer metastasis.

项目概要转移是癌症发病率和死亡率的主要原因，与过去相比，结果几乎没有改善过去十年，这一点在胃肠道癌症中尤为明显，其中肝脏转移最多。我们发现癌细胞在肝脏中的扩散和生长是常见的。依赖于肝细胞引导的可逆生态位环境的形成，肝细胞是主要功能为了支持这一假设，我们发现原发性肿瘤释放可溶性因子激活肝脏中的肝细胞。肝细胞通过急性期反应物做出反应，在肝脏中编排一个生态环境，以中性粒细胞和骨髓细胞的募集以及细胞外基质的沉积为基础在缺乏这种促转移蛋白的情况下，这种环境支持癌细胞的播种和定植。尽管巨噬细胞是第一个进入细胞休眠状态的利基，但播散性癌细胞在肝脏中进入细胞休眠状态。防止肝脏转移的防线，它们的生物学特性也在生态位的形成过程中因此，我们的研究结果确定了肝脏内的细胞间网络。肝细胞通过准备支持癌细胞“播种”的“土壤”来对癌症的发展做出反应。我们的最终目标是设计新的疗法来解决促转移生态位并重新引导肝脏然而，这需要从促转移环境到抗转移环境来治疗和预防癌症转移。了解肝细胞指导生态位形成的信号并确定策略能够逆转利基的促转移潜力，因此，在目标 1 中，我们将定义下游。在目标 2 中，我们将确定肝细胞协调肝脏中促转移生态位形成的信号。将肝脏中的微环境从促转移转变为抗转移的策略在目标 3 中，我们将研究肝细胞对肝脏癌细胞休眠的影响以及细胞毒性化疗的疗效。这些互补的目标将为开发旨在调节肝脏的抗- 转移潜力作为预防和治疗癌症转移的策略。