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Mechanical regulation of the microenvironmental niche in skin tumorigenesis

皮肤肿瘤发生中微环境生态位的机械调节

基本信息

批准号：
10486877
负责人：
Kandice Tanner
金额：
$ 33.89万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10486877
关键词：
Architecture Atypia Basement membrane Benign Breast Cells Cellular Morphology Chemicals Clinical Dermis Disease Dysplastic Nevus Environment Epidermis Evolution Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibronectins Genes Genetic Histologic Immune In Vitro Individual Larynx Lesion Lung Malignant Neoplasms Mechanics Metastatic Melanoma Metastatic Neoplasm to the Bone Molecular Mus Neoplasm Metastasis Nevus Non-Small-Cell Lung Carcinoma Organ Outcome Pathway interactions Precancerous melanosis Primary Carcinoma Primary Neoplasm Proteins Proteomics Radial Radial Growth Phase Regulation Signal Pathway Signal Transduction Site Skin Solid Stromal Cells Structure Subcutaneous Tissue Testing Time Tissues Tumor Suppressor Proteins Urothelium Vertical Growth Phase Visualization Zebrafish biophysical properties cancer type cell motility cell type chemical property cytokine in vivo Model keratinocyte mechanical properties melanocyte melanoma morphogens neoplastic cell overexpression three-dimensional modeling tissue tropism transcriptome sequencing tumor tumorigenesis

项目摘要

The genetic factors governing tissue tropism in cancer metastasis have been identified in some solid cancers, but the contributions of the genetic differences, the dynamic interactions between tumor cells, and the microenvironment of the metastasizing cells- the "metastatic niche" are not well understood. Molecular characterization of the microenvironments from the major sites of metastases indicates both similarities and distinct differences, which may influence colonization across types of cancers. Specifically, cross-comparison of lung versus bone metastases revealed that there were some expressed genes in common whereas others were distinct. But, whether these pathways are specific to lung versus other organs have not been identified. Similarly, RNAseq and proteomic analysis across solid primary carcinomas of different tissue origins such as breast, laryngeal, urothelial and non- small cell lung cancers when compared to normal adjacent tissue consistently show an overexpression of secreted extracellular matrix proteins such as fibronectin (FN) . Using genetically modified mice, the contributions of the immune and stromal cells towards creating a "pro-tumor" environment have been established at sites of metastasis. These cells assist tumor colonization by secreting ECM proteins and other cytokines. However, direct visualization of the metastatic niche has largely been observed from histopathological analysis as discrete snapshots in time. What is needed is the real-time visualization of the establishment of the metastatic niche to understand why these cells are able to colonize these organs.

在一些实体癌中已经确定了控制癌症转移中的组织向性的遗传因素，但是遗传差异、肿瘤细胞之间的动态相互作用和转移细胞的微环境-“转移小生境”的贡献还没有很好地理解。来自主要转移部位的微环境的分子表征表明相似性和明显差异，这可能影响不同类型癌症的定植。具体来说，肺转移与骨转移的交叉比较显示，有一些表达的基因是共同的，而另一些是不同的。但是，这些途径是否特异于肺与其他器官尚未确定。类似地，当与正常相邻组织相比时，不同组织来源的实体原发性癌如乳腺癌、喉癌、尿路上皮癌和非小细胞肺癌的RNAseq和蛋白质组学分析一致地显示分泌的细胞外基质蛋白如纤连蛋白（FN）的过表达。使用遗传修饰的小鼠，已经在转移部位建立了免疫细胞和基质细胞对创造“促肿瘤”环境的贡献。这些细胞通过分泌ECM蛋白和其他细胞因子来协助肿瘤定殖。然而，转移灶的直接可视化主要是从组织病理学分析中观察到的离散快照。我们需要的是转移性小生境建立的实时可视化，以了解为什么这些细胞能够定植在这些器官上。