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：
9153967
负责人：
Kandice Tanner
金额：
$ 27.16万
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/9153967
关键词：
Atypia Basement membrane Benign Breast Cells Cellular Morphology Chemicals Clinical Dermis Dysplastic Nevus Environment Epidermis Evolution Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibronectins Genes Genetic Imagery Immune 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 Property Proteins Proteomics Radial Radial Growth Phase Regulation Signal Pathway Signal Transduction Site Skin Solid Staging Stromal Cells Subcutaneous Tissue Testing Time Tissues Tumor Suppressor Proteins Vertical Growth Phase base biophysical properties cancer type cell motility cell type chemical property cytokine keratinocyte melanocyte melanoma morphogens neoplastic cell overexpression 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.

在某些固体癌症中已经鉴定出了控制癌症转移中组织乳液的遗传因素，但是遗传差异的贡献，肿瘤细胞之间的动态相互作用以及转移细胞的微环境 - “转移性niche”尚不清楚。来自主要转移的主要位点的微环境的分子表征表明相似性和明显的差异，这可能会影响跨癌症类型的定植。具体而言，肺与骨转移的交叉比较表明，有些具有共同的基因，而另一些则是不同的。但是，尚未鉴定出这些途径是否特定于肺与其他器官。同样，与正常的邻近组织相比，不同组织起源的固体原代癌的RNASEQ和蛋白质组学分析始终显示出分泌的细胞外基质蛋白，例如纤维蛋白（FN）。使用转基因的小鼠，在转移部位建立了免疫和基质细胞对创建“亲肿瘤”环境的贡献。这些细胞通过分泌ECM蛋白和其他细胞因子来帮助肿瘤定植。然而，从组织病理学分析中观察到转移性裂市场的直接可视化是时间病理学分析。需要的是建立转移性细分市场的实时可视化，以了解为什么这些细胞能够定居这些器官。