MAKING HOLES: IDENTIFYING HOW METASTATIC CANCER CELLS APPLY FORCE TO INVADE THEIR MICROENVIRONMENT

The process of invasion is of special importance in cancer metastasis, the main cause of cancer mortality. Cells typically penetrate a matrix by degrading it or by squeezing through pores. However, cell mechanics and cell-applied forces during the initial stages of metastatic penetration, as metastatic cells indent a substrate, are still unknown. We focus only on mechanical-interactions, by measuring the forces that cells apply to an impenetrable, synthetic 2-dimensional gel-matrix; gels are non-degradable polyacrylamide with sub-micron pores. We show that single metastatic breast-cancer cells will apply force to an impenetrable gel, and indent it in attempted invasion, when the gel is in the appropriate stiffness range [1]; benign cells do not indent gels. The metastatic cells require gels that are soft enough to indent, yet stiff enough to grip and generate force on. Cells pull the gels inwards and upwards, at grip handles, bringing the nucleus into the indentation concavity. We reveal a coordinated role for the nucleus and the cytoskeleton during gel indentation. The actin, nucleus, and microtubules reorganize in sequence, with actin at the cell’s leading edge [2]. Cells repeatedly attempt penetration over several hours and then relocate, indicating an advanced mechano-transduction feedback loop. The systems and analysis approaches shown here reveal cell adaptation, force application mechanisms, and can potentially serve as a diagnostic/prognostic platform.

[1] Revital Kristal-Muscal, Liron Dvir, and Daphne Weihs, “Metastatic cancer cells tenaciously indent impenetrable, soft substrates”, New Journal of Physics 15, 035022 (2013).

[2] Liron Dvir, Ronen Nissim, Martha Alvarez-Elizondo, and Daphne Weihs, “Quantitative measures to reveal coordinated cytoskeleton-nucleus reorganization during in vitro invasion of cancer cells”, New Journal of Physics 17, 043010 (2015).