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FLOAT System to Study Salivary Gland Cancer Invasion

FLOAT 系统研究唾液腺癌侵袭

基本信息

批准号：
9763563
负责人：
David K Ann
金额：
$ 21.63万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-14 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763563
关键词：
3-Dimensional Acinar Cell Address Animal Model Architecture Attention Autophagocytosis Bioinformatics CRISPR/Cas technology Cancer Biology Cancer Patient Cell Culture Techniques Cells Color Comorbidity Complex Connective Tissue Data Deposition Desmoplastic Diet Disease Distant DsRed Ductal Epithelial Cell Environment Extracellular Matrix Fatty acid glycerol esters Fibroblasts Fibrosis Fluorescence Gene Expression Genes Genetic Transcription Gland Goals Green Fluorescent Proteins Heterogeneity Human Immune Immunocompetent Implant Inflammation Invaded Investigation Label Lasers Lesion Life Link Lipids Localized Malignant Neoplasm Malignant Neoplasms Malignant neoplasm of salivary gland Mass Spectrum Analysis Methods Modeling Molecular Monitor Mus Neoplasms Obesity Organ Pathway interactions Play Prevalence Process Prognostic Marker Proteins Reporting Research Research Personnel Residual state Resources Role Salivary Salivary Gland Neoplasms Salivary Glands Site Solid Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Stromal Cells Structure Submandibular gland Sucrose System Testing Therapeutic Time Tissue imaging Tissues Transgenic Animals Transgenic Model Transplantation Tumor Cell Invasion Work allotransplant cancer cell cancer type design diagnostic biomarker follow-up genetic signature host neoplasm interaction improved in vitro Model in vivo innovation insight ionization migration neoplastic cell novel diagnostics novel strategies novel therapeutics outcome forecast preservation prognostic assays recruit response spatiotemporal three dimensional structure transplant model treatment strategy tumor tumor microenvironment tumor progression

项目摘要

The goal of this R21 is to use our newly developed dual-color Fluorescence-tracing Orthotopic AlloTransplantation (FLOAT) system to investigate the molecular mechanisms underlying salivary gland cancer (SGC) progression. Bioinformatics studies of human SGC have identified putative molecular pathways that regulate tumor invasion, but follow-up analysis has proved challenging. Cell culture models are limited by the lack of a native tumor microenvironment and transgenic animal models are limited by resource-intensive methods and difficulties distinguishing tumor cells from the surrounding stroma. Therefore, new approaches that allow researchers to rapidly test molecular hypotheses, while preserving the native 3D structure of the tumor microenvironment, are needed. Furthermore, these models need to consider the impact of other comorbidities in distant sites, such as obesity. Our proposal will address this need using the FLOAT system, a simple and experimentally tractable orthotopic transplantation model, which allows researchers to visualize implanted salivary tumor cells and the adjacent microenvironment, to accurately model many aspects of in vivo SGC progression. This system utilizes DsRed fluorescence to label salivary tumor cells, which are transplanted into the salivary glands of green fluorescent protein-expressing mice. Dual-color fluorescence allows researchers to rapidly evaluate the tumor cells relative to the adjacent stroma. Our preliminary data demonstrate that the FLOAT system was useful for demonstrating that intrinsic tumor autophagy capacity modulates the architecture of tumor-bearing glands and survival. We will now use the FLOAT system to evaluate how obesity promotes local invasion of primary SGC lesions in vivo. Local invasion is required for SGC progression, but this multifaceted process is not well understood. Also, although changes in both tumor cells and the surrounding matrix have been reported during cancer progression, a direct mechanistic link between diet-induced obesity and accelerated SGC progression has not been established. We hypothesize that diet-induced obesity exacerbates SGC local invasion by inducing changes in the tumor microenvironment that permit or enhance local invasion. Given the crucial role of the tumor microenvironment in cancer progression, we further predict that the effect of diet-induced obesity on the type and activity of cells in the tumor microenvironment facilitates SGC invasion. In Aim 1, we will use the FLOAT system to test the effects of diet-induced obesity on SGC local invasion, gene expression, and lipid profiles. This Aim includes 3D matrix-assisted laser desorption/ionization (MALDI)-tissue-imaging mass spectrometry (TIMS) analysis of lipid profile heterogeneity in the invading tumor. In Aim 2, we will use the FLOAT system to test the effects of diet-induced obesity on fibrosis and inflammation in the microenvironment. The FLOAT system represents a powerful first step for both visualizing and distinguishing the heterogeneous components of host-tumor interaction during local invasion and a new system for efficiently testing novel therapeutics.

此R21的目标是使用我们新开发的双色双折射跟踪原位同种异体移植（FLOAT）系统，以研究唾液腺的分子机制胃癌（SGC）进展。人类SGC的生物信息学研究已经确定了推定的分子途径调节肿瘤侵袭，但后续分析已证明具有挑战性。细胞培养模型受限于由于缺乏天然肿瘤微环境和转基因动物模型，区分肿瘤细胞和周围间质的方法和困难。因此，新方法这使研究人员能够快速测试分子假设，同时保留了细胞的天然3D结构。肿瘤微环境是必需的。此外，这些模型还需要考虑其他因素的影响。远处的合并症，如肥胖。我们的建议将使用浮动系统来解决这一需求，一个简单的，实验上易于处理的原位移植模型，它允许研究人员可视化植入的唾液腺肿瘤细胞和邻近的微环境，以准确地模拟体内的许多方面， SGC进展。该系统利用DsRed荧光标记唾液肿瘤细胞，进入绿色荧光蛋白表达小鼠的唾液腺。双色荧光允许研究人员快速评估肿瘤细胞相对于邻近基质。我们的初步数据证明FLOAT系统可用于证明固有的肿瘤自噬能力，调节肿瘤腺体的结构和存活。我们现在将使用FLOAT系统来评估肥胖如何促进体内原发性SGC病变的局部侵袭。需要局部侵入， SGC进展，但这个多方面的过程还没有得到很好的理解。此外，虽然肿瘤的变化细胞和周围的基质已经报道在癌症进展过程中，一个直接的机制联系，饮食诱导的肥胖和加速的SGC进展之间的关系尚未确定。我们假设饮食诱导的肥胖通过诱导肿瘤的变化加剧了SGC局部侵袭，微环境允许或增强局部侵入。考虑到肿瘤的重要作用微环境在癌症进展中的作用，我们进一步预测饮食诱导的肥胖对癌症类型的影响。并且肿瘤微环境中的细胞活性促进SGC侵袭。在目标1中，我们将使用浮动系统来测试饮食诱导的肥胖对SGC局部侵袭、基因表达和脂质谱的影响。该Aim包括3D基质辅助激光解吸/电离（MALDI）-组织成像质谱在侵袭性肿瘤中脂质谱异质性的TIMS分析。在目标2中，我们将使用FLOAT系统，测试饮食诱导的肥胖对微环境中纤维化和炎症的影响。浮子系统代表了可视化和区分异构组件的强大的第一步在局部侵袭过程中宿主-肿瘤相互作用的新系统和有效测试新疗法的新系统。