Tumor microenvironments determing migration, dissemination and dormancy

描述（由申请人提供）：转移的传统观点是，它是由一个类似于达尔文进化的过程引起的，涉及肿瘤细胞的自然选择，这些肿瘤细胞能够在治疗期间和在远处迁移和存活。在该模型中，选择表现出稳定遗传变化的肿瘤细胞，所选择的细胞是非常罕见的，局部的，并在肿瘤进展后期引起转移。最近发展的新技术，包括基于高密度微阵列的表达谱，多光子活体成像和收集和表征的迁移性肿瘤细胞从活肿瘤和骨髓播散的肿瘤细胞（DTC）的患者，已经挑战了这种传统的转移模型。新技术表明，转移能力是在肿瘤进展的早期阶段获得的，比达尔文模型预测的要早得多，在原发性肿瘤的大部分中编码，它是高度可塑性的，涉及基因表达的瞬时变化。这些结果导致了转移的微环境模型。如果在进展过程中选择原发性肿瘤中的稳定遗传变化导致的肿瘤进展有助于诱导支持侵袭性和转移性表型的基因表达的瞬时变化所需的微环境，则微环境和达尔文模型可以协调。也就是说，肿瘤微环境启动诱导肿瘤细胞迁移、存活和转移的基因的瞬时表观遗传表达。乳腺肿瘤中这种微环境的例子是细胞外基质密度、炎症和缺氧。为了研究这些微环境及其对转移表型的影响，我们组建了一个多学科团队，他们将利用他们的专业知识进行合作：1。肿瘤细胞的命运图，以确定从不同的自发迁移的肿瘤细胞，以及纳米装置产生的可溶性因子衍生的微环境，是否在靶器官中具有不同的迁移，传播，休眠和生长模式。2.在原发性肿瘤和DTC中，以单细胞分辨率确定这些微环境的空间和时间范围以及功能后果3.分离和表征肿瘤细胞特殊群体的代谢组学、基因组学和表观基因组学，例如播散部位的迁移和休眠肿瘤细胞。4.研究ECM依赖性迁移/侵袭、休眠和增殖肿瘤细胞表型。5.将关键观察结果扩展到人类乳腺和头颈部鳞状肿瘤。

DESCRIPTION (provided by applicant): A traditional view of metastasis is that it results from a process similar to Darwinian evolution involving the natural selection of tumor cells that are capable of migration and survival during treatment and at distant sites. In this model the selection of tumor cells exhibiting stable genetic changes occurs, the selected cells are very rare, local and cause metastasis late in tumor progression. The recent development of new technologies, including high-density microarray based expression profiling, multiphoton intravital imaging and the collection and characterization of migratory tumor cells from live tumors and bone marrow disseminated tumor cells (DTCs) from patients, have challenged this traditional model of metastasis. The new technologies indicate that metastatic ability is acquired at much earlier stages of tumor progression than predicted by the Darwinian model, is encoded throughout the bulk of the primary tumor, it is highly plastic and involves transient changes in gene expression. These results have led to the micro-environment model of metastasis. The micro-environment and Darwinian models can be reconciled if tumor progression resulting from the selection of stable genetic changes in the primary tumor during progression, contributes the micro-environments necessary to induce the transient changes in gene expression that support the invasive and metastatic phenotype. That is, the tumor micro-environment initiates the transient epigenetic expression of genes that induce tumor cell migration, survival and metastasis. Examples of such micro-environments in breast tumors are extracellular matrix density, inflammation, and hypoxia. To study these micro-environments and their effects on metastatic phenotype, we have assembled a multidisciplinary team who will collaborate using their special expertise to: 1. fate map tumor cells to determine if tumor cells migrating from different spontaneous, and nano-device generated soluble factor-derived micro-environments, have different migration, dissemination, dormancy and growth patterns in target organs. 2. Determine the spatial and temporal extent and functional consequences of these micro-environments at single cell resolution in vivo in primary tumors and in DTCs 3. Isolate and characterize the metabolomics, genomics and epigenomics of special populations of tumor cells such as the migratory and dormant tumor cells in disseminated locations. 4. Investigate ECM-dependent migratory/invasive, dormant and proliferative tumor cell phenotypes. 5. Extend key observations to human breast and head and neck squamous tumors.