Metastasis predicts poor prognosis in cancer patients. It has been recognized that specific tumor microenvironment defines cancer cell metastasis, whereas the underlying mechanisms remain elusive. Here we show that Galectin-7 is a crucial mediator of metastasis associated with immunosuppression. 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 tumor progression. Deletion of Galectin-7 in NR-S1M cells significantly suppressed lymph node and lung metastasis without affecting primary tumor growth. Therefore, Galectin-7 is a crucial mediator of tumor metastasis of SCC, which is educated in the immune-suppressed tumor areas, and may be a potential target of cancer immunotherapy.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.