Regulation of Cancer Cell Metastasis by Mechanical Force

机械力调节癌细胞转移

• 批准号: 1002165
• 负责人: Taher Saif
• 金额: $ 36万
• 依托单位: University of Illinois at Urbana-Champaign
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1002165&HistoricalAwards=false
• 关键词: Regulation; Cancer; Cell; Metastasis; Mechanical

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.

该项目的目的是通过(A)测量细胞力的历史，以及(B)探索力传导到转移的分子机制来揭示机械力和微环境在肿瘤转移中的作用。PI最近发现，人结肠癌(HCT-8)细胞在体外培养在具有适当机械软性的底物上时，表现出分离的、转移样表型(MLP)。这一新的发现表明，转移的开始可能从根本上与肿瘤的机械微环境有关。智力优势：假设依赖僵硬的转移是由细胞响应其机械微环境产生的时间力历史(在几天内)介导的。细胞将延长的力信号传递到生化途径，这些途径决定了它们向高度转移状态的转变。这一假设将通过：(1)通过开发一种新的细胞力传感器，在单细胞或亚细胞尺度上测量HCT-8细胞的细胞力(细胞-细胞，细胞-底物)在几天到几周的时间演变。(2)通过同时询问细胞在经历类转移转变时的细胞骨架和分子特征来寻找MLP的分子机制。更广泛的影响：尽管癌症患者的早期诊断和治疗都有了显著改善，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范式，它有可能为当前的武器库增加新的抗转移疗法。这项研究将通过(1)开发一门新的研究生水平的跨学科课程，(2)为当地儿童开发一个实践教学模块--S博物馆，(3)招收来自不同背景的苏格兰皇家大学学生，(4)培养一个研究生领导小组，(5)开发一个网页来传播即将开发的新知识和工具，将这项研究与教育和外展相结合。