Spatial co-elevation of IGF1R and STMN1 associates with metastatic progression in osteosarcoma

Background: Osteosarcoma metastasis remains the leading cause of patient mortality, and current therapeutic strategies offer limited benefit for metastatic disease. Identifying metastasis-associated signaling programs is essential for developing more effective interventions. Methods: We integrated single-cell RNA sequencing, spatial transcriptomics, ligand-receptor interaction analysis, and functional assays to define molecular programs associated with osteosarcoma progression. Clinical cohorts were used to evaluate associations with metastasis and survival. In vitro and in vivo models were applied to validate mechanistic insights and therapeutic response. Results: High IGF1R and STMN1 expression strongly correlated with distant metastasis and poor prognosis. Single-cell communication analysis revealed enhanced crosstalk between STMN1⁺ osteosarcoma cells and cancer-associated fibroblasts (CAFs), predominantly driven by IGF-mediated signaling. Spatial transcriptomics confirmed the co-localization and coordinated upregulation of IGF1R and STMN1 in metastatic niches. Functional assays demonstrated that stromal IGF1/IGF2 activation of IGF1R increases STMN1 expression, and stronger spatial co-elevation of these molecules reflects enhanced coordination that facilitates tumor dissemination. Dual targeting of IGF1R and STMN1 significantly suppressed osteosarcoma invasion and metastatic outgrowth in both in vitro and in vivo models. Conclusions: This study identifies the IGF1R-STMN1 axis as a mechanistically coherent and spatially reinforced driver of osteosarcoma metastasis. The spatial co-elevation of IGF1R and STMN1 marks metastatic niches and represents a promising therapeutic vulnerability, offering new avenues for improving outcomes in osteosarcoma.