Sarcoma metastasis: distinct biological principles beyond the carcinoma paradigm

Sarcomas are rare in adults but constitute a substantial fraction of pediatric malignancies and are characterized by a high propensity for hematogenous dissemination and poor outcomes once metastatic. Yet, most mechanistic understanding of metastasis derives from carcinomas and is frequently extrapolated to sarcomas despite major biological differences. This review synthesizes current evidence on sarcoma metastasis and highlights key knowledge gaps across the metastatic cascade. It frames sarcomas as malignancies often arising from mesenchymal stromal cells, whose intrinsic motility, plasticity, and stem-like features may predispose transformed cells to dissemination without requiring a classic epithelial-to-mesenchymal transition program. The concept of metastasis-initiating cells is discussed in the context of sarcoma cancer stem cell biology, clonal evolution, and epigenetic reprogramming, emphasizing that the relative genomic simplicity of certain pediatric sarcomas driven by recurrent fusion oncogenes may provide powerful models to dissect metastasis dependencies. The review examines how the sarcoma tumor microenvironment, often immunosuppressive and macrophage-rich, may shape invasion, intravasation, survival in circulation, extravasation, and organotropism, particularly the strong predilection for pulmonary metastasis. It summarizes emerging data on circulating tumor cells and complementary liquid biopsy approaches, while underscoring technical limitations caused by sarcoma heterogeneity and lack of robust markers. Finally, the review appraises current treatment limitations for metastatic sarcoma and argues that improved mechanistic resolution, especially of plasticity, epigenetic states, microenvironmental interactions, and dormancy, will be essential to identify actionable vulnerabilities and improve outcomes for patients with disseminated disease.