Upregulation of Galectin-7 in specific tumor microenvironment contributes to squamous cell carcinoma metastasis

Metastasis predicts poor prognosis in patients with esophageal squamous cell carcinoma, whereas the regulatory mechanism of metastasis remains largely unknown. In this study, by using murine tumor metastasis model and spatial transcriptome analysis, we aimed to decipher the molecular basis of metastasis. In a syngeneic mouse squamous cell carcinoma (SCC) model of NR-S1M cells, we isolated metastasized NR-S1M cells from lymph nodes in tumor-bearing mice and established metastatic NR-S1M cells in in vitro culture. RNA-seq analysis revealed that interferon gene signature was markedly downregulated in metastatic NR-S1M cells compared with parental cells, and in vivo NR-S1M tumors heterogeneously developed focal immunosuppressive areas featured by deficiency of anti-tumor immune cells. Spatial transcriptome analysis (Visium) for the NR-S1M tumors revealed that various pro-metastatic genes were significantly upregulated in immunosuppressive areas when compared to immunocompetent areas. Notably, Galectin-7 was identified as a novel metastasis-driving factor. Galectin-7 expression was induced during tumorigenesis particularly in the microenvironment of immunosuppression, and extracellularly released at later stage of tumors progression. Deletion of Galectin-7 in NR-S1M cells significantly suppressed lymph node and lung metastasis without affecting primary tumor growth. Therefore, Galectin-7 plays a crucial role in tumor metastasis of SCC as a pro-metastatic factor in the immune-suppressed tumor areas and may be a potential target of cancer immunotherapy.