Analysis of the Signaling and Mechanical Cues Promoting Invasion in Melanoma

促进黑色素瘤侵袭的信号传导和机械线索分析

• 批准号: 8230348
• 负责人: DOUGLAS A LAUFFENBURGER
• 金额: $ 43.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230348
• 关键词: Accounting; Address; Attention; Automobile Driving; Behavior; Biological Assay; Biological Markers; Biomimetics; Blood Vessels; Breslow Thickness; Cancer Biology; Categories; Cell Adhesion; Cell Communication; Cell Culture Techniques; Cell Line; Cell Proliferation; Cells; Cellular Morphology; Characteristics; Chemicals; Clinical; Collaborations; Complex; Cues; Data Set; Dependence; Detection; Diagnosis; Disease; Disseminated Malignant Neoplasm; Early Diagnosis; Endocrine; Environment; Event; Exercise; Extracellular Matrix; Fiber; Gel; Genetic; Genotype; Growth; Growth Factor; Human; In Vitro; Incidence; Individual; Intervention; Libraries; Link; Malignant Neoplasms; Maps; Measures; Mechanics; Mediating; Mediator of activation protein; Melanoma Cell; Metastatic Melanoma; Methodology; Methods; Modeling; Molecular; Nanostructures; Nature; Outcome; Output; Pathway Analysis; Patients; Phenotype; Physiological; Process; Radial; Regulation; Research; Research Proposals; Series; Side; Signal Transduction; Site; Skin; Skin Cancer; Skin Tissue; Speed; Staging; Structure; Techniques; Testing; Thick; Time; Tissue Model; Tissues; Traction; Universities; base; cancer type; cell behavior; cell motility; clinically relevant; combinatorial; computerized data processing; cytokine; data acquisition; environmental change; follow-up; functional outcomes; in vivo; melanoma; migration; nanostructured; novel; paracrine; prognostic; programs; response; small hairpin RNA; tool; tumor

DESCRIPTION (provided by applicant): Metastatic melanoma is the deadliest form of skin cancer and one of the most aggressive cancer types, capable of rapid spreading out of the primary site. This proposal is aimed at analyzing the combined effect of changes in the genetic and signaling states of melanoma cells and the cell micro-environment on the degree of cell aggressiveness and putative metastatic potential. The main hypothesis underlying our analysis is that aggressiveness of melanoma cells is determined by a combination of different factors, with a major contribution from the state of cell microenvironment, including the structure of the ECM and the presence of soluble chemical factors. Alteration in the cell micro-environment, such as alignment of ECM fibers, can permit an otherwise non-metastatic cell to become more aggressive, whereas the aggressiveness of ostensibly metastatic cell can be moderated by environmental changes and targeted intervention in regulation of signaling cascades. We also hypothesize that cells can actively interact with the micro-environment not only by secreting or degrading ECM components, but by actively exercising forces on and thus aligning ECM fibers in the direction of a nearest anchor point, including the vasculature. This can in turn generate more anisotropic forces allowing cells to deform ECM even more and ultimately take advantage of the re-aligned ECM structure to migrate towards blood vessels. We will test these hypotheses in close collaboration with ICBP@MIT, first taking advantage of the new methodologies using shRNA libraries to perturb genetic targets (Aim 1) along with a broad range of environmental perturbations and then use the state of the art statistical analysis tools available at ICBP@MIT to reduce complexity of resulting datasets, linking multiple environmental and genetic perturbation to aggressive cell behavior (Aim 2), We will use several novel assays in the process, increasing manageability of data acquisition and processing, as well as enhancing the biomimetic nature of experimentation. Finally, we will test the predictions arising from the models developed in Aim 2 through a series of tests, ranging from cell culture to tissue construct to model tissue levels (Aim 3). We anticipate that the proposed research will reveal new, previously unanticipated interplay between environmental and genetic factors in control of metastatic events in melanoma and potentially suggest new ways of battling this deadly disease. The results might also have relevance to other metastatic cancers. PUBLIC HEALTH RELEVANCE: Early detection is further hampered by the lack of biomarker-based detection tests. One of the critical reasons for this situation is the lack of understanding of the mechanisms underlying the metastatic switch in melanoma and the mechanisms allowing metastatic cells to successfully and quickly navigate all the hurdles associated with the metastatic spread, including effective migration to and intravasation into the blood vessels. This project is aimed at filling this critical gap.

描述（由申请人提供）：转移性黑色素瘤是皮肤癌的最致命形式，也是最具侵略性的癌症类型之一，能够快速扩散到主要部位。该建议旨在分析黑色素瘤细胞的遗传和信号传导状态变化以及细胞微环境对细胞侵袭性和推定转移潜能程度的综合作用。我们分析的主要假设是，黑色素瘤细胞的侵略性取决于不同因素的组合，以及细胞微环境状态的主要贡献，包括ECM的结构和可溶性化学因子的存在。细胞微环境的改变，例如ECM纤维的比对，可以使原本非转移性细胞变得更具侵略性，而表面上转移性细胞的侵略性可以通过环境变化和针对性的干预来调节信号级联的调节。我们还假设细胞不仅可以通过分泌或降解ECM组件来主动与微环境相互作用，还可以通过积极地锻炼力，从而使ECM纤维在最近的锚点（包括脉管系统）的方向上对齐。这反过来可以产生更多的各向异性力，从而使细胞更加变形ECM，并最终利用重新对准的ECM结构向血管迁移。 We will test these hypotheses in close collaboration with ICBP@MIT, first taking advantage of the new methodologies using shRNA libraries to perturb genetic targets (Aim 1) along with a broad range of environmental perturbations and then use the state of the art statistical analysis tools available at ICBP@MIT to reduce complexity of resulting datasets, linking multiple environmental and genetic perturbation to aggressive cell behavior (Aim 2), We will use several novel在此过程中的测定，提高了数据获取和处理的可管理性，并增强了实验的仿生性质。最后，我们将通过一系列测试在AIM 2中开发的模型产生的预测，从细胞培养到组织构建体到模型组织水平（AIM 3）。我们预计，拟议的研究将揭示出在黑色素瘤转移事件控制中的环境和遗传因素之间的新的，以前意外的相互作用，并有可能提出与这种致命疾病作斗争的新方法。结果也可能与其他转移性癌症有关。 公共卫生相关性：缺乏基于生物标志物的检测测试进一步阻碍了早期检测。这种情况的关键原因之一是缺乏理解 黑色素瘤转移开关的基础机制以及允许转移细胞成功并快速导航与转移扩散相关的所有障碍，包括有效迁移到血管中的所有障碍。这 项目旨在填补这一关键空白。