LCAL4-FUS cooperation switches on MMP13 and drives osteolytic bone metastasis in breast cancer

Patients with advanced breast cancer (BC) often experience bone metastasis, leading to severe skeletal complications and a significant decline in prognosis. However, the molecular mechanisms underlying BC bone metastasis remain largely unexplored. This study identified the long non-coding RNA LCAL4 as specifically upregulated in bone-metastatic BC, where it serves as an independent predictor of poor survival. Gain- and loss-of-function experiments in intracardiac and intratibial mouse models demonstrate that ectopic LCAL4 expression markedly enhances BC cell-mediated osteolytic bone metastasis. Mechanistically, LCAL4 acts as a molecular scaffold, directly binding the RNA/DNA-binding protein FUS, promoting its nuclear accumulation, and recruiting it to the MMP13 promoter. The LCAL4-FUS ribonucleoprotein complex then recruits RNA polymerase II and induces H3K4me3 deposition, thereby activating MMP13 transcription. Secreted MMP13 stimulates osteoclast differentiation and enhances bone-resorptive activity. The release of TGF-β from resorbed bone further accelerates tumor proliferation, establishing a self-reinforcing cycle that drives osteolytic metastasis. Notably, genetic disruption of the LCAL4-FUS-MMP13 pathway significantly suppresses BC bone metastasis. These findings highlight the pivotal role of the LCAL4-FUS-MMP13 axis in BC skeletal colonization and osteolytic progression, highlighting its potential as a therapeutic target for managing BC bone metastasis.