LATS1/2–integrin axis confers tumor-generated forces that activate neighboring fibroblasts

Tumors generate various forces during growth and progression, which, in turn, promote tumor development. Although fibroblasts are considered the primary force generators in the tumor microenvironment, recent studies have shown that cancer cells also generate considerable tensile force. However, the role of these forces in the tumor microenvironment and the pathways regulating this process remain largely unknown. Here, we demonstrate that the Hippo pathway kinases LATS1/2 in cancer cells are essential for collective force generation and fibroblast activation via extracellular matrix-mediated cell–cell interactions. In murine breast cancer 4T1 spheroids, deletion of LATS1/2 dampens force generation and disrupts the reorganization of surrounding collagen matrix. The LATS1/2-mediated mechanical forces of the tumor are required for fibroblast activation and differentiation into mechanoresponsive fibroblasts. Mechanistically, LATS1/2 regulate tumor force generation through the expression of the collagen receptor integrins. Our findings not only identify the Hippo pathway as a critical regulator of tumor force generation, but also suggest potential strategies for targeting the Hippo pathway in cancer therapy from the mechanobiological perspective, offering new avenues in the fight against cancer. Overall design: Comparative gene expression profiling analysis between cancer spheroids generated from wild-type or LATS1/2 double knock-out 4T1 cell lines.

肿瘤在生长与进展过程中会产生多种力学作用力，而这些作用力反过来又会促进肿瘤的发生发展。尽管此前认为成纤维细胞（fibroblasts）是肿瘤微环境（tumor microenvironment）中主要的力学作用力产生者，但近期研究表明，癌细胞同样能够产生可观的拉伸应力。然而，这些作用力在肿瘤微环境中所发挥的作用，以及调控该过程的信号通路，目前仍未得到充分阐明。
本研究证实，癌细胞内的Hippo通路（Hippo pathway）激酶LATS1/2，可通过细胞外基质（extracellular matrix, ECM）介导的细胞-细胞相互作用，在集体力学作用力产生与成纤维细胞活化过程中发挥关键作用。在小鼠乳腺癌4T1细胞球（spheroids）模型中，敲除LATS1/2会削弱力学作用力的产生，并破坏周围胶原蛋白基质的重构。肿瘤细胞通过LATS1/2介导的力学作用力，是成纤维细胞活化并分化为机械响应性成纤维细胞所必需的。从机制上来说，LATS1/2通过调控胶原蛋白受体整合素（integrins）的表达，来调节肿瘤的力学作用力产生。本研究结果不仅证实Hippo通路是肿瘤力学作用力产生的关键调控因子，还从力学生物学（mechanobiology）视角为靶向Hippo通路的癌症治疗提供了潜在策略，为抗癌研究开辟了新方向。
实验整体设计：对野生型或LATS1/2双敲除的4T1细胞系所构建的癌细胞球进行比较基因表达谱分析。