The role of mechanics in tumor progression and malignancy

描述(申请人提供)：力学在肿瘤进展和恶性肿瘤中的作用在过去的几十年里，各种研究都集中在微环境在癌症进展中的重要性这一观点上。具体地说，与微环境的正常相互作用可以抑制肿瘤的形成和生长，而正常环境的破坏可以支持肿瘤的进展和转移。最近的研究表明，微环境的机械特性在这种相互作用中发挥了重要作用，但细胞感知环境机械的机制以及这种相互作用在癌症中是如何改变的仍不清楚。在这个项目中，我们将在重组的三维藻酸盐凝胶基质中研究微环境的力学对乳腺上皮细胞增殖、迁移和恶性程度的影响。利用藻酸盐凝胶可以精确控制粘弹性和图例密度，并且已经建立了一种精确测量凝胶形成的键合细胞数量的技术。我们将探讨基质弹性、粘弹性和配体密度对非恶性乳腺上皮细胞增殖和迁移的影响，并观察癌前和恶性乳腺上皮细胞这种反应的变化。然后，我们将开发一种技术来测量细胞对藻酸盐凝胶施加的应变和压力，并使用这些测量来阐明细胞物理探测其微环境的机制。这些测量也将在具有不同恶性表型的细胞系中进行，以确定这一机制的差异是否与对微环境的不同敏感性有关。这里提出的实验将提供对癌症恶性本质的一般洞察，以及细胞感知其机械微环境的机制。这种洞察力可能与癌症恶性肿瘤的诊断相关，并为抑制肿瘤进展和恶性肿瘤提供新的技术建议。

DESCRIPTION (provided by applicant): The role of mechanics in tumor progression and malignancy over the last few decades, various studies have converged upon the idea that the microenvironment is important in the progression of cancer. Specifically, the normal interactions with the microenvironment can suppress tumor formation and growth, while disruption of the normal context can support the progression and metastasis of tumors. More recent studies have suggested that the mechanical properties of the microenvironment plays an important role in this interaction, but the mechanism by which cells sense the mechanics of the environment, and how this interaction is altered in cancer remains unknown. In this project, we will investigate the effect of mechanics of the microenvironment on mammary epithelial cell proliferation, migration, and malignancy in reconstituted three dimensional alginate gel matrices. Precise control over viscoelasticity and legend density is possible with alginate gels, and a technique to precisely measure the number of bonds cells form with the gel has been established. We will probe the effect of matrix elasticity, viscoelasticity, and ligand density on proliferation and migration of the non-malignant mammary epithelial cells, and see how this response changes for pre-malignant and malignant mammary epithelial cells. Then we will develop a technique to measure strains and stresses exerted by the cells on the alginate gels, and use these measurements to elucidate the mechanism by which the cells physically probe their microenvironment. These measurements will also be conducted across cell lines with different malignant phenotypes to determine whether differences in this mechanism are correlated with different sensitivities to the microenvironment. The experiments proposed here will provide general insight into the nature of cancer malignancy as well as the mechanism by which cells sense their mechanical microenvironment. Such insight could be relevant for diagnosis of cancer malignancy, and suggest new techniques for suppressing tumor progression and malignancy.