Regulation of Cancer Cell Metastasis by Mechanical Force

该项目的目标是通过（a）测量细胞力历史，和（B）寻找力传递到转移的分子机制，来揭示机械力和微环境在癌症转移中的作用。PI最近发现，当在具有适当机械柔软度的基质上培养时，人结肠癌（HCT-8）细胞在体外表现出解离的转移样表型（MLP）。这一新的发现表明，转移的发病可能从根本上联系到机械microenvironment的tumor.Intellectual merit：它是假设刚度依赖性转移介导的时间力的历史的细胞（天），他们产生的响应于他们的机械微环境。细胞将长时间的力信号传递给生化途径，决定它们向高转移状态的转变。该假设将通过以下方式进行检验：（1）通过开发新型细胞力传感器，在单细胞或亚细胞规模上测量HCT-8细胞在数天至数周内的细胞力（细胞-细胞，细胞-底物）的时间演变。(2)通过同时询问细胞的细胞骨架和分子特征来寻找MLP的分子机制，因为它们经历了转移样转变。更广泛的影响：尽管在癌症患者的早期诊断和治疗方面都有了显着改善，但转移仍然是死亡的主要原因。了解机械微环境如何调节负责转移的癌细胞生物学过程代表了一种新的发展模式，该模式有可能为当前的武器库添加新的抗转移治疗剂。这项研究将与教育和推广相结合，（1）开发一个新的研究生水平的跨学科课程，（2）为当地儿童开发一个动手教学模块？的博物馆，（3）招聘来自不同背景的REU学生，（4）培养研究生领导小组，（5）开发一个网页，传播新的知识和工具，以开发。

The objective of the project is to unravel the role of mechanical forces and microenvironment in cancer metastasis by (a) measuring the cellular force history, and (b) searching for the molecular mechanism of force transduction to metastasis. The PIs have recently discovered that human colon carcinoma (HCT-8) cells exhibit a dissociative, metastasis-like phenotype (MLP) in vitro when cultured on substrates with appropriate mechanical softness. This novel finding suggests that the onset of metastasis may be fundamentally linked to the mechanical microenvironment of the tumor.Intellectual merit: It is hypothesized that the stiffness dependent metastasis is mediated by the temporal force histories of the cells (over days) that they generate in response to their mechanical micro-environment. Cells transduce the prolonged force signal to biochemical pathways that determine their transition to highly metastatic state. The hypothesis will be tested by:(1) Measuring temporal evolution of cell force (cell-cell, cell-substrate) for HCT-8 cells over days to weeks at a single cell or subcellular scale by developing a novel cell force sensor. (2) Searching for molecular mechanisms for MLP by simultaneously interrogating cytoskeletal and molecular signatures of the cells as they go through metastatic-like transition. Broader impact: Despite the significant improvement in both the early diagnosis and treatment of cancer patients, metastasis is still the major cause of mortality. Understanding how the mechanical microenvironment regulates cancer cell biological processes responsible for metastasis represents a newly developing paradigm that has the potential to add novel anti-metastasis therapeutics to the current arsenal. The research will be integrated with education and outreach by (1) developing a new graduate level interdisciplinary course, (2) developing a hands-on instructional module for local children?s museum, (3) recruiting REU students from diverse backgrounds, (4) fostering a graduate student leadership group, (5) developing a web page to disseminate the new knowledge and tools to be developed.