Durotaxis - the ability of cells to sense and migrate along stiffness gradients - is important for embryonic development and has been implicated in pathologies including fibrosis and cancer. Although cellular processes can sometimes turn toward softer environments, durotaxis at the level of cells has thus far been observed exclusively as migration from soft to stiff regions. The molecular basis of durotaxis, especially the factors that contribute to different durotactic behaviors in various cell types, are still inadequately understood. With the recent discovery of 'optimal stiffness,' where cells generate maximal traction forces on substrates in an intermediate stiffness range, we hypothesized that some migratory cells may be capable of moving away from stiff environments and toward matrix on which they can generate more traction. Combining hydrogel-based stiffness gradients, live-cell imaging, genetic manipulations, and computational modeling, we found that cells move preferentially toward their stiffness optimum for maximal force transmission. Importantly, we directly observed biased migration toward softer environments, i.e. 'negative durotaxis,' in human glioblastoma cells. This directional migration did not coincide with changes in FAK, ERK or YAP signaling, or with altered actomyosin contractility. Instead, integrin-mediated adhesion and motor-clutch dynamics alone are sufficient to generate asymmetric traction to drive both positive and negative durotaxis. We verified this mechanistically by applying a motor-clutch-based model to explain negative durotaxis in the glioblastoma cells and in neurites, and experimentally by switching breast cancer cells from positive to negative durotaxis via talin downregulation. Our results identify the likely molecular mechanisms of durotaxis, with a cell's contractile and adhesive machinery dictating its capacity to exert traction on mechanically distinct substrates, directing cell migration.

中文翻译：

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负旋转度：细胞向较软环境移动

Durotaxis-细胞感知和沿着硬度梯度迁移的能力-对于胚胎发育很重要，并已牵涉到包括纤维化和癌症在内的病理学中。尽管细胞过程有时可以转向较软的环境，但迄今为止，仅在细胞水平上的双旋性是从软区域向硬区域的迁移。仍然没有充分理解durotaxis的分子基础，尤其是在各种细胞类型中导致不同durotactic行为的因素。随着“最优刚度”的最新发现，即细胞在中等刚度范围内在基质上产生最大牵引力，我们假设某些迁徙细胞可能能够脱离刚性环境，向能够在其上产生更大牵引力的基质移动。结合基于水凝胶的刚度梯度，活细胞成像，遗传操作和计算模型，我们发现细胞优先朝其刚度最佳方向移动，以实现最大的力传递。重要的是，我们直接观察到人胶质母细胞瘤细胞中偏向软环境的迁移，即“负度旋转”。这种定向迁移与FAK，ERK或YAP信号的变化或放线肌球蛋白的收缩性改变均不符。取而代之的是，整联蛋白介导的粘附力和运动离合器动力学仅足以产生不对称的牵引力，从而驱动正和负durotaxis。我们通过应用基于运动离合器的模型来说明胶质母细胞瘤细胞和神经突中的负度durotaxis，从而机械地验证了这一点，并通过塔林下调将乳腺癌细胞从阳性durotaxis转换为阴性durotaxis。我们的研究结果确定了durotaxis的可能分子机制，其中细胞的收缩和粘附机制决定了其在机械不同的基质上施加牵引力的能力，从而指导细胞迁​​移。