细胞附着、施加作用力和迁移穿越其周围环境的能力是组织再生和癌症转移的决定因素。细胞在这一过程中施加的生理收缩力的作用和相关的分子机制尚未完全理解。因此，我们的目标是澄清转化和浸润性成纤维细胞在施加于其环境的细胞外力或变形细胞核的胞内力以及这些力之间的联系是否存在缺陷，并指示控制的潜在分子机制。通过共聚焦、荧光显微镜和牵引力显微镜，结合计算分析，显示相比于正常对照细胞，浸润性成纤维细胞施加在环境上的最大收缩力增加，细胞核上的胞内力减少。通过tubacin处理和siRNA介导的HDAC6沉默，失去了HDAC6活性的作用，可逆转转化和浸润细胞的尺寸减小、形状更圆以及迁移缺陷，使之恢复到正常状态。然而，只有tubacin介导而不是siRNA沉默能将浸润细胞施加在环境上的力恢复到正常，对核内力没有影响。我们观察到环境力和细胞核力呈弱正相关，除了HDAC6 siRNA处理细胞，其之间呈弱负相关。相比于对照组，转化和浸润性成纤维细胞显示出更多且较小的细胞-基质粘附物，而tubacin处理和HDAC6沉默都不能使这一表型恢复到正常，反而进一步增加。这突显了细胞收缩力的控制可能需要HDAC6的不同功能，而不是细胞粘附、扩展和形状的控制。这些数据与来自细胞外环境到细胞核受力传导存在缺陷参与转移的可能性一致，这种机制依赖于HDAC6。据我们所知，我们的研究结果首次揭示了成纤维细胞中变形细胞外环境和细胞核的细胞力之间的相关性，扩展了我们对细胞产生收缩力并促进细胞入侵和转移的理解。版权所有 © 2023 López-Guajardo、Zafar、Al Hennawi、Rossi、Alrwaili、Medcalf、Dunning、Nordgren、Pettersson、Estabrook、Hawkins和Gad。

The capacity of cells to adhere to, exert forces upon and migrate through their surrounding environment governs tissue regeneration and cancer metastasis. The role of the physical contractile forces that cells exert in this process, and the underlying molecular mechanisms are not fully understood. We, therefore, aimed to clarify if the extracellular forces that cells exert on their environment and/or the intracellular forces that deform the cell nucleus, and the link between these forces, are defective in transformed and invasive fibroblasts, and to indicate the underlying molecular mechanism of control. Confocal, Epifluorescence and Traction force microscopy, followed by computational analysis, showed an increased maximum contractile force that cells apply on their environment and a decreased intracellular force on the cell nucleus in the invasive fibroblasts, as compared to normal control cells. Loss of HDAC6 activity by tubacin-treatment and siRNA-mediated HDAC6 knockdown also reversed the reduced size and more circular shape and defective migration of the transformed and invasive cells to normal. However, only tubacin-mediated, and not siRNA knockdown reversed the increased force of the invasive cells on their surrounding environment to normal, with no effects on nuclear forces. We observed that the forces on the environment and the nucleus were weakly positively correlated, with the exception of HDAC6 siRNA-treated cells, in which the correlation was weakly negative. The transformed and invasive fibroblasts showed an increased number and smaller cell-matrix adhesions than control, and neither tubacin-treatment, nor HDAC6 knockdown reversed this phenotype to normal, but instead increased it further. This highlights the possibility that the control of contractile force requires separate functions of HDAC6, than the control of cell adhesions, spreading and shape. These data are consistent with the possibility that defective force-transduction from the extracellular environment to the nucleus contributes to metastasis, via a mechanism that depends upon HDAC6. To our knowledge, our findings present the first correlation between the cellular forces that deforms the surrounding environment and the nucleus in fibroblasts, and it expands our understanding of how cells generate contractile forces that contribute to cell invasion and metastasis.Copyright © 2023 López-Guajardo, Zafar, Al Hennawi, Rossi, Alrwaili, Medcalf, Dunning, Nordgren, Pettersson, Estabrook, Hawkins and Gad.