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 forces. However, the roles that these forces play in the tumor microenvironment and the pathways regulating this process remain largely unknown. Here, we demonstrated that the Hippo pathway-associated 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 4 T1 spheroids, the deletion of LATS1/2 dampened force generation and disrupted reorganization of the surrounding collagen matrix. LATS1/2-mediated mechanical forces of tumors are required for fibroblast activation and differentiation into mechanoresponsive fibroblasts. Mechanistically, LATS1/2 regulate tumor force generation through the expression of 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 it in cancer therapy from a mechanobiological perspective, offering new avenues in the fight against cancer.