Hypoxia-driven metastatic progression in synovial sarcoma: insights from SYO-1 and SW982 models

Synovial sarcoma (SS) is a rare but aggressive soft tissue malignancy characterized by a high rate of pulmonary metastasis and limited response to conventional therapies. Hypoxia, a common feature of tumor microenvironment, has been implicated in cancer progression, yet its specific contribution to metastatic dissemination in SS remains insufficiently characterized.

We investigated the effects of hypoxia on metastatic behavior in two SS cell lines: SYO-1 (SS18-SSX2 fusion-positive) and SW982 (fusion-negative). Cells were cultured under hypoxic (O₂ < 1%) and normoxic (21% O₂) conditions, followed by reoxygenation. Expression of hypoxia-responsive and metastasis-related genes (e.g., HIF-1α, CA9, VEGF, IGF2, ADM, YB-1, TGF-β1) was assessed via qRT-PCR. To evaluate in vivo metastatic potential, a lung colonization model was established by injecting pretreated cells into the tail veins of immunodeficient (NMRI nu/nu) mice.

Hypoxia significantly upregulated canonical HIF-1α targets in both cell lines, with SYO-1 showing stronger and more sustained induction, particularly of CA9 and VEGF. In vivo, SYO-1 cells formed significantly more micrometastatic lung lesions compared to SW982, with distinct perivascular clustering and signs of early intravasation. SW982 cells exhibited limited, diffuse infiltration and lower hypoxia-induced gene activation. These differences suggest that the SS18-SSX fusion may synergize with hypoxia signaling to enhance metastatic potential. Notably, HIF-1α, CA9, and IGF2 expression correlated with metastatic capacity, while TGF-β1 expression declined under hypoxia, indicating a dynamic regulation of prometastatic pathways.

Our findings demonstrate that hypoxia promotes SS metastasis through activation of HIF-1α and related pathways. Fusion-positive SS cells appear particularly responsive to hypoxic cues, suggesting that targeting hypoxia-induced signaling could be a promising strategy to inhibit metastasis in SS. These results provide mechanistic insight into SS progression and support the integration of hypoxia-targeted therapies into future treatment strategies.