Oncogenic LPP facilitates focal adhesion maturation in response to mechanical tension and regulates the Hippo signaling.

LIM family proteins play pivotal roles in mechano-transduction, a process often dysregulated in human cancers. However, the functions and mechanisms of LIM proteins in tumor biology remain insufficiently characterized. In this study, we demonstrate that the LIM family protein Lipoma Preferred Partner (LPP) is amplified and its expression is upregulated in various human cancer samples, correlating with poor prognosis. We show that LPP is essential for tumor growth and metastasis across multiple tumor models, including xenografts and patient-derived organoids. Mechanistically, mechanical stimulation induces the recruitment of LPP to focal adhesions (FAs) via VASP in tumor cells, promoting Paxillin-dependent FA maturation. Furthermore, LPP inactivates the core kinases of the Hippo pathway, LATS1/2, through PP2A complex-mediated dephosphorylation, thereby leading to the activation of YAP. Collectively, our findings reveal the mechanistic basis of LPP-mediated mechano-transduction and demonstrate how its upregulation drives tumor progression. These insights may have important implications for cancer diagnosis and therapy.