Carcinoma Cell Hyaluronan as a Therapeutic Target in Metastasis

癌细胞透明质酸作为转移治疗靶点

基本信息

批准号：
9250092
负责人：
David Kevin Wood
金额：
$ 16.27万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9250092
关键词：
Adhesions Animal Model Architecture Binding Biological Assay Biological Models Blood Circulation Blood Vessels Breast Cancer Cell Breast Carcinoma Breast cancer metastasis CD44 Antigens Carcinoma Cell Adhesion Cell Line Cell membrane Cell surface Cells Complex Coupled Cytoskeleton Data Development Distant Endothelial Cells Endothelium Epigenetic Process Event Extracellular Matrix Extravasation Failure Frustration Genetic Goals Gold Growth Human Hyaluronan Hyaluronidase Image Impairment In Vitro Individual Lead Link Lipids Malignant - descriptor Malignant Epithelial Cell Malignant neoplasm of prostate Metastatic Carcinoma Metastatic breast cancer Microfluidics Modeling Molecular Weight Monitor Neoplasm Metastasis Noise Oncogenic Pathway interactions Phenotype Physiological Polymers Positioning Attribute Primary Neoplasm Process Reagent Receptor Activation Role Signal Pathway Signal Transduction Site Solid Speed System Testing Time Tissues Up-Regulation Work base cell motility design in vitro Model in vivo metastatic process migration mouse model neoplastic cell new therapeutic target novel novel therapeutics prevent public health relevance receptor screening spatiotemporal targeted treatment therapeutic target tool tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Metastasis, which represents the major cause of frustration and failure in therapy, remains the least understood stage of cancer progression. One of the difficulties in studying later stages of metastasis is the lack of appropriate models of the complex metastatic process. To overcome this challenge, we have developed a microfluidic system that recapitulates critical stages of metastasis while allowing for real time stimulation of cell phenotype and real time imaging of the metastatic process. The microfluidic model recapitulates critical aspects of the ectopic site, including a vascular compartment with physiologic flow and functional endothelium and a solid ECM-rich tissue compartment. In this work, we will use this platform to elucidate the importance of HA-dependent mechanisms in tumor cells as drivers of metastasis and ultimately to develop the microfluidic model system as a screening tool for identifying novel anti-metastatic reagents. Our working hypothesis is that HA synthesis and pericellular coat formation by metastatic carcinoma cells confers a `stromal independent' phenotype to enhance metastasis formation. Mechanistically the prediction is that this facilitates survival in the circulation and promotes carcinoma cell adhesion to endothelial cells, subsequent extravasation, and invasion and growth within the parenchyma of tissues harboring metastatic lesions. Within this work, we will specifically: (1) optimize our microfluidic platform to quantify the metastatic potential of breast cancer cells; (2) quantify the effects of altering HA synthesis by metastatic carcinoma cells on tumor cells arrest, extravasation and growth both in vitro and in vivo. While HA synthesis by carcinomas has been linked with malignant progression, we hypothesize that it is the formation of a pericellular rich matrix that positions plasma membrane receptors, organizes the cytoskeleton and functions to maintain survival. Preliminary data support this hypothesis and this will be further tested by limiting HA synthesis and artificially restoring the pericellular matrix, using lipid coupled HA that will intercalate into the plasma membrane. We will evaluate key oncogenic signaling and survival pathways in cells (both suspended and adherent) that have, or do not have, an endogenous or artificial HA rich pericellular matrix. The prediction is that cells with a pericellular HA matrix ill in fact maintain activated oncogenic pathways, independent of adhesion, that will be inhibited by preventing the formation of a pericellular HA rich matrix. Beyond this specific mechanism of metastasis, this model should help focus on critical events in metastasis and ultimately speed the discovery of new therapeutic targets to block rate limiting steps in this process.

描述（由申请人提供）：转移是治疗受挫和失败的主要原因，它仍然是癌症进展中最不为人所知的阶段，研究转移的后期阶段的困难之一是缺乏适当的模型。为了克服这一挑战，我们开发了一种微流体系统，可以重现转移的关键阶段，同时允许实时刺激微流体模型概括了异位部位的细胞表型和实时成像，包括具有生理流动和功能性内皮的血管区室以及富含 ECM 的固体组织区室。阐明肿瘤细胞中 HA 依赖性机制作为转移驱动因素的重要性，并最终开发微流体模型系统作为识别新型抗转移试剂的筛选工具。假设转移性癌细胞的HA合成和细胞周膜形成赋予了“基质独立”表型以增强转移形成，从机制上预测这有利于循环中的存活并促进癌细胞粘附到内皮细胞、随后的外渗和侵袭。在这项工作中，我们将具体：（1）优化我们的微流体。量化乳腺癌细胞转移潜力的平台；（2）量化转移性癌细胞改变HA合成对肿瘤细胞在体外和体内停滞、外渗和生长的影响，而癌症的HA合成与恶性有关。在进展过程中，我们发现细胞周丰富基质的形成可以定位质膜受体、组织细胞骨架和维持生存的功能，初步数据支持这一假设，并将通过限制 HA 合成和进一步验证这一点。使用嵌入质膜的脂质偶联 HA 人工恢复细胞周基质，我们将评估具有或不具有富含内源性或人工 HA 的细胞周的关键致癌信号传导和存活途径。预测是，具有细胞周 HA 基质的细胞实际上会维持激活的致癌途径，而与粘附无关，除了这种特定的细胞周 HA 基质之外，该途径将受到抑制。转移机制，该模型应有助于关注转移中的关键事件，并最终加速新治疗靶点的发现，以阻止该过程中的速率限制步骤。