Cell contractility‐driven multicellular nodule formation

Abstract

We demonstrate that characteristic nodules emerge in cultures of various malignant pleural mesothelioma (MPM) cell lines. Instead of excessive local cell proliferation, these nodules arise by Myosin II‐driven cell contractility. Acto‐myosin rich stress cables, lined up across cell membranes and thus mechanically linking several cells, are prevalent in sections of surgical MPM samples as well as in nodules formed by cultured MPM cells. A cell‐resolved elasto‐plastic model can explain both the formation dynamics and the observed morphologies of the nodules. The model also predicts the speed of formation as determined by the degree of mechanical tension between neighboring cells, and the stability of cell‐substrate adhesion: For small contractile forces, nodules are slow to develop and localized at the boundary of cell free areas. In contrast, high intra‐layer tension quickly transforms all cell‐coated areas into dense clusters interconnected by multicellular strands. Model simulations also indicate that a decreased stability of cell‐substrate adhesions favors the formation of fewer, but larger clusters. Accordingly, several cell types cultured on a melleable substrate, such as matrigel, exhibits this cell contractility‐driven patterning process. Used as a bioassay for intercellular contractility, analysis of the spatio‐temporal dynamics of nodule formation helps to identify functional effects of the myosin inhibitors.Support or Funding InformationR01‐GM102801