Negative durotaxis: cell movement toward softer environments

• Published in: Nature materials 2022-07, Vol.21 (9), p.1081-1090
• Main Authors: Isomursu, Aleksi, Park, Keun-Young, Hou, Jay, Cheng, Bo, Mathieu, Mathilde, Shamsan, Ghaidan, Fuller, Benjamin, Kasim, Jesse, Mohsen Mahmoodi, M., Lu, Tian Jian, Genin, Guy M., Xu, Feng, Lin, Min, Distefano, Mark, Ivaska, Johanna, Odde, David J.
• Format: Article
• Language: English
• ISSN: 1476-1122; 1476-4660
• DOI: 10.1038/s41563-022-01294-2

How cells sense tissue stiffness to guide cell migration is a fundamental question in development, fibrosis and cancer. Although durotaxis – traditionally defined as cell migration toward increasing substrate stiffness – is well established, it remains unknown whether individual cells can migrate toward softer environments. Using microfabricated stiffness gradients, we observed directed migration of U-251MG glioma cells toward lower stiffness. This ‘negative durotaxis’ did not coincide with changes in canonical mechanosensitive signaling or actomyosin contractility. Instead, motor-clutch-based modeling predicted migration toward cell-intrinsic ‘optimal stiffness’, where cells generate maximal traction. As predicted by the model, negative durotaxis was selectively disrupted and even reversed by partial inhibition of actomyosin contractility. Conversely, positive durotaxis was switched to negative experimentally by lowering the optimal stiffness via downregulation of a key clutch component, talin. Our results identify the molecular mechanism driving context-dependent positive or negative durotaxis, determined by a cell’s contractile and adhesive machinery.