Blebbing Driven or Actin Protrusive-Force Driven Cancer Cell Migration

点击翻译按钮获取中文摘要

Cell migration in 3D extracellular matrices is a prerequisite for tissue assembly and regeneration, immune cell trafficking, and diseases such as cancer. Moreover, the process of metastasis depends on the migration of single cancer cells. The interstitial migration is a cyclic process consisting of multiple steps such as the actin polymerization-dependent pseudopod protrusion at the leading edge, the integrin-mediated adhesion to the extracellular matrix, the contact-dependent extracellular matrix degradation through the cleavage evoked by cell surface proteases, the actomyosin-facilitated contraction of the cell body increasing longitudinal tension and the retraction of the cell rear followed by the translocation of the cell body. This describes only one particular migration mode of metastatic cells: the protrusive mode, whereas there are still other modes, in particular the blebbing mode. Which invasion mode is favored by certain cancer cells and under specific environmental conditions is under discussion. However, the capability of cancers to metastasize depends on the cells ability to migrate into connective tissue, adhere, and possibly transmigrate through the endothelium. It is still elusive what determines the mode of invasion and how the appearance or the switch between the different modes is regulated. The choice of the invasion mode is supposed to have an important impact on the regulation of the basement membrane or endothelial barrier-crossing potential of cancer cells and their invasion speed. How successful a migrating cell overcomes different obstacles found in dense matrices depends highly on its mechanical properties and how it generates its protrusive forces. Thus forces and material properties determine the favorable invasive migration mode for cancer cells. We have established that cancer cells with certain mechanical properties such as contractile force transmission and generation invade more efficiently into 3D extracellular matrices compared to less contractile cancer cells. Our project will elucidate major mechanisms by which cancer cells regulate their invasion mode and what role the microenvironmental properties such as mechanics and structure of the extracellular matrix play. To investigate this, we will dissect the crosstalk between invasion modes and environmental constraints such as mesh or pore size, stiffness of the entire cell, the plasma membrane and the extracellular matrix, and the proteomics of the cellular adhesion machinery as well as extracellular protein composition by determining the influence of cytoskeletal and plasma membrane stiffness, cell adhesion and cell contractility on invasive cell motility and to what extent this factors favor protrusive or blebbing-based motion. Finally, our data will expand our understanding of the respective contribution of mechanical properties of cancer cells and their microenvironment to the invasive and metastatic behavior of epithelial-derived cancers.