ZC3HAV1 promotes osteosarcoma metastasis through TSC1 mRNA destabilization and mTORC1 pathway activation

Abstract Pulmonary metastasis is the leading cause of mortality in osteosarcoma patients, yet the molecular mechanisms that sustain invasive malignancy within metastatic niches remain poorly understood. Through analysis of single-cell transcriptomic data from osteosarcoma lung metastases and clinical survival datasets, this study identifies a pro-invasive malignant cell state associated with poor prognosis and nominates ZC3HAV1 as a top candidate gene. Functional experiments demonstrate that ZC3HAV1 promotes osteosarcoma cell migration, invasion, and lung metastatic colonization both in vitro and in vivo. Mechanistically, the ZC3HAV1 encoded RNA binding protein ZAP forms a complex with the RNA helicase DHX30 to bind the 3’UTR of the tumor suppressor TSC1 mRNA, destabilizing the transcript and thereby relieving TSC mediated inhibition of mTORC1 signaling, which in turn activates a pro-metastatic transcriptional program. Clinically, elevated ZC3HAV1 expression correlates with increased mTORC1 pathway activity and heightened sensitivity to rapamycin treatment. These findings not only establish ZC3HAV1 as a key driver of osteosarcoma metastasis but also reveal a novel paradigm in which tumor cells hijack an evolutionarily conserved antiviral RNA decay machinery to fuel metastatic progression. This work identifies ZC3HAV1 as a predictive biomarker and provides a translational rationale for mTORC1 targeted therapy in ZC3HAV1 high osteosarcoma patients.