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. Comparative gene expression profiling analysis between cancer spheroids generated from wild-type or LATS1/2 double knock-out 4T1 cell lines.