Multicellular contractility contributes to the emergence of mesothelioma nodules

Julia Tarnoki-Zach,Ildiko Kovacs,Dona Greta Isai,Paul Stockhammer,Andras Czirok,Elod Mehes,Walter Berger,Zoltan Neufeld,Sandor Paku,Balint Szeder,Edina Bugyik,Balazs Hegedus,Balazs Dome,Sufi Mary Thomas

doi:10.1038/s41598-020-76641-x

Abstract

Malignant pleural mesothelioma (MPM) has an overall poor prognosis and unsatisfactory treatment options. MPM nodules, protruding into the pleural cavity may have growth and spreading dynamics distinct that of other solid tumors. We demonstrate that multicellular aggregates can develop spontaneously in the majority of tested MPM cell lines when cultured at high cell density. Surprisingly, the nodule-like aggregates do not arise by excessive local cell proliferation, but by myosin II-driven cell contractility. Prominent actin cables, spanning several cells, are abundant both in cultured aggregates and in MPM surgical specimens. We propose a computational model for in vitro MPM nodule development. Such a self-tensioned Maxwell fluid exhibits a pattern-forming instability that was studied by analytical tools and computer simulations. Altogether, our findings may underline a rational for targeting the actomyosin system in MPM.

Highlights

An anisotropic contractile activity gives rise to cell intercalation, when cell adjacency changes in such a way that the whole tissue elongates in one direction while it narrows along the perpendicular direction[10,11]
Mesenchymal cells can contract the surrounding extracellular matrix (ECM): if a cell aggregate is placed on the surface of a collagen gel, cell traction reorganizes the collagen and creates bundles of ECM that radiate away from the a ggregate[13,14]
To study the collective behavior of malignant pleural mesothelioma (MPM) cells, we performed long term live-cell imaging of confluent cultures. In such long term cultures around half of the cell lines established from MPM patients form macroscopic nodules (Supplementary Table S1), similar to nodules appearing on the pleural surfaces of mesothelioma patients and in orthotopic models of certain mesothelioma cell lines (Fig. 1a)

Summary

Introduction

An anisotropic contractile activity gives rise to cell intercalation, when cell adjacency changes in such a way that the whole tissue elongates in one direction while it narrows along the perpendicular direction[10,11]. Mesenchymal cells can contract the surrounding extracellular matrix (ECM): if a cell aggregate is placed on the surface of a collagen gel, cell traction reorganizes the collagen and creates bundles of ECM that radiate away from the a ggregate[13,14] This observation has led to the development of the mechano-chemical theory of pattern formation[15,16] according to which cells exert traction forces on an underlying deformable substrate and the resulting strain transports (convects) both cells and the ECM. With stochastic simulations we examine the effects of key model parameters, the stability of cell-cell and cell-substrate adhesions, and the magnitude of cell-exerted contractile forces Taken together, these studies may point to an important role of cell contractility in the pathophysiology of MPM

Methods

Results

Conclusion