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Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression

Oncogene volume 41, pages 5319–5330 (2022)Cite this article

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Abstract

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.

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Fig. 1: Interferon gene signature is downregulated in metastatic NR-S1M cells.
Fig. 2: Malignant NR-S1M tumors develop focal immunosuppressive areas.
Fig. 3: Spatial transcriptome (ST) analysis of NR-S1M tumors.
Fig. 4: Identification of immunosuppressive region with metastatic potential.
Fig. 5: Identification of Galectin-7 as a potential metastasis-driving factor.
Fig. 6: Ablation of Galectin-7 in NR-S1M cells alleviates metastasis.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank all members of our laboratories for technical assistance and helpful discussions.

Funding

KKuba is supported by the Kaken [20H03426, 20K21566, 22K19551] from Japanese Ministry of Science and the Naito Foundation. JA is supported by the Kaken [20K16153, 22K06907], SM is supported by the Kaken [20K09048], YI is supported by the Kaken [17H06179], and TY is supported by the Kaken [20K07285] from Japanese Ministry of Science. This research was also supported by AMED under Grant Number JP 21lm0203079.

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Authors and Affiliations

  1. Department of Biochemistry and Metabolic Science, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan

    Jianbo An, Yushi Nagaki, Midori Hoshizaki, Kohei Kemuriyama, Tomokazu Yamaguchi & Keiji Kuba

  2. Department of Surgery, Akita University Graduate School of Medicine, Akita, Japan

    Yushi Nagaki, Satoru Motoyama, Kohei Kemuriyama & Yoshihiro Minamiya

  3. Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, 277-8562, Japan

    Yuta Kuze & Yutaka Suzuki

  4. Department of Medical Biology, Akita University Graduate School of Medicine, Akita, Japan

    Midori Hoshizaki & Takashi Ebihara

  5. Laboratory of Regulation of Intractable Infectious Diseases, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka, 567-0085, Japan

    Yumiko Imai

  6. Department of Pharmacology, Kyushu University Graduate School of Medical Sciences, Fukuoka, 812-8582, Japan

    Keiji Kuba

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JA, YN, SM and KKuba conceived the study. JA, YN, SM, MH, KKemuriyama, TY, TE, YM, YI and KKuba conducted experiments and/or analyzed data. YK and YS conducted deep sequencing and analyzed the data. JA and KKuba wrote the manuscript with input from all authors.

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Correspondence to Keiji Kuba.

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An, J., Nagaki, Y., Motoyama, S. et al. Identification of Galectin-7 as a crucial metastatic enhancer of squamous cell carcinoma associated with immunosuppression. Oncogene 41, 5319–5330 (2022). https://doi.org/10.1038/s41388-022-02525-1

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