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

An, Jianbo; Nagaki, Yushi; Motoyama, Satoru; Kuze, Yuta; Hoshizaki, Midori; Kemuriyama, Kohei; Yamaguchi, Tomokazu; Ebihara, Takashi; Minamiya, Yoshihiro; Suzuki, Yutaka; Imai, Yumiko; Kuba, Keiji

doi:10.1038/s41388-022-02525-1

Cited by 6 publications

(8 citation statements)

References 56 publications

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“…We found that this lectin induces highly immunosuppressive M-MDSCs in the TME, thus providing a possible explanation for the poor T-cell stimulatory activity of myeloid cells in SCC patients [59]. In this regard, recent evidence identified Gal-7 as a pro-metastatic gene highly expressed in immunosuppressive SCC microenvironments [60]. Additional mechanisms underlying Gal-7 effects, such as those involving altered intracellular functions should be further explored.…”

Section: Discussionmentioning

confidence: 68%

Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs

et al. 2023

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Non-melanoma skin cancer (NMSC) has risen dramatically as a result of chronic exposure to sunlight ultraviolet (UV) radiation, climatic changes and clinical conditions associated with immunosuppression. In spite of considerable progress, our understanding of the mechanisms that control NMSC development and their associated molecular and immunological landscapes is still limited. Here we demonstrated a critical role for galectin-7 (Gal-7), a β-galactoside-binding protein preferentially expressed in skin tissue, during NMSC development. Transgenic mice (Tg46) overexpressing Gal-7 in keratinocytes showed higher number of papillomas compared to WT mice or mice lacking Gal-7 (Lgals7−/−) when subjected to a skin carcinogenesis protocol, in which tumor initiator 7,12-dimethylbenz[a]anthracene (DMBA) and tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) were sequentially administered. RNAseq analysis of Tg46 tumor lesions revealed a unique profile compatible with cells of the myelomonocytic lineage infiltrating these tumors, an effect that was substantiated by a higher number of CD11b+Gr1+ cells in tumor-draining lymph nodes. Heightened c-Met activation and Cxcl-1 expression in Tg46 lesions suggested a contribution of this pathway to the recruitment of these cells. Remarkably, Gal-7 bound to the surface of CD11b+Ly6ChiLy6Glo monocytic myeloid cells and enhanced their immunosuppressive activity, as evidenced by increased IL-10 and TGF-β1 secretion, and higher T-cell inhibitory activity. In vivo, carcinogen-treated Lgals7−/− animals adoptively transferred with Gal-7-conditioned monocytic myeloid cells developed higher number of papillomas, whereas depletion of these cells in Tg46-treated mice led to reduction in the number of tumors. Finally, human NMSC biopsies showed increased LGALS7 mRNA and Gal-7 protein expression and displayed transcriptional profiles associated with myeloid programs, accompanied by elevated CXCL1 expression and c-Met activation. Thus, Gal-7 emerges as a critical mediator of skin carcinogenesis and a potential therapeutic target in human NMSC.

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Section: Discussionmentioning

confidence: 68%

Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs

et al. 2023

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“…By using anti-Ly6G neutralizing antibody, we demonstrated for the first time the role of neutrophils in the development of SCC. We observed that the amount of neutrophils in NR-S1M tumors increased significantly after 2 weeks of implantation (An et al, 2022). We administered the neutralizing antibody for multiple times, and depletion of neutrophils successfully confined tumor growth.…”

Section: Discussionmentioning

confidence: 91%

“…We have previously observed that malignant NR‐S1M cells (the cells isolated from metastatic sites), but not parental ones, upregulated Csf3 expression (An et al, 2022). NR‐S1M tumor is highly heterogeneous, and its functional properties varied by distinct regions.…”

Section: Discussionmentioning

confidence: 99%

“…Since our previous RNA-seq analysis for murine SCC model of NR-S1M cells had shown that G-CSF was significantly upregulated in the metastatic NR-S1M cells (An et al, 2022), we investigated the expression of G-CSF in human ESCC to assess its clinical relevance. We performed immunohistochemistry of G-CSF in the tissue microarrays (TMA) of 177 primary tumors obtained from the ESCC patients without preoperative chemoradiotherapy to investigate a role of the G-CSF in ESCC.…”

Section: Expression Of G-csf Is Associated With Poor Prognosis Of Esc...mentioning

confidence: 99%

“…In addition, it has been noticed that G‐CSF is highly expressed in several types of SCC (Gutschalk et al, 2006; Karagiannidis et al, 2021; Kawano et al, 2015). Furthermore, our recent study had shown that G‐CSF was highly upregulated in the metastatic murine SCC NR‐S1M cells, which were isolated from metastasized LNs in mice (An et al, 2022), suggesting a potential role of G‐CSF in SCC progression. Nevertheless, whether and how G‐CSF contributes to ESCC malignancy remains largely unknown.…”

Section: Introductionmentioning

confidence: 99%

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Squamous cell carcinoma‐derived G‐CSF promotes tumor growth and metastasis in mice through neutrophil recruitment and tumor cell proliferation, associated with poor prognosis of the patients

Kemuriyama

Motoyama

et al. 2023

Genes to Cells

Self Cite

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Tumor‐derived G‐CSF is a well‐known factor to aggravate disease progression in various types of cancers. In this study, we investigated a role of G‐CSF in squamous cell carcinoma (SCC). High expression of G‐CSF in the tumor tissues of esophageal SCC (ESCC) patients correlated with poor prognosis. Murine SCC NR‐S1M cells produce considerable amount of G‐CSF, which expression is correlated with its metastatic potentials. Deletion of G‐CSF in NR‐S1M cells mitigated tumor growth and metastasis to lymph node and lung of subcutaneous NR‐S1M tumors in the mice. Mechanistically, G‐CSF enhanced cell proliferation in autocrine manner in vitro, whereas in NR‐S1M tumor‐bearing mice, accumulation of plasma G‐CSF was associated with expansion of peripheral neutrophils, which led to a decreased proportion of CD8+ T cells. Antibody depletion of neutrophils restored the number of CD8+ T cells and modestly suppressed tumor outgrowth, albeit no changes in distant metastasis. We propose that G‐CSF produced by NR‐S1M cells facilitates tumor progression in mice through bi‐functional effects to promote neutrophil recruitment and tumor cell proliferation, which may render poor prognosis to the ESCC patients with high G‐CSF expression.

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Proteomic analysis of pleomorphic dermal sarcoma reveals a fibroblastic cell of origin and distinct immune evasion mechanisms

Klein,

Tolkach,

Reinhardt

et al. 2024

Sci Rep

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Pleomorphic dermal sarcomas are infrequent neoplastic skin tumors, manifesting in regions of the skin exposed to ultraviolet radiation. Diagnosing the entity can be challenging and therapeutic options are limited. We analyzed 20 samples of normal healthy skin tissue (SNT), 27 malignant melanomas (MM), 20 cutaneous squamous cell carcinomas (cSCC), and 24 pleomorphic dermal sarcomas (PDS) using mass spectrometry. We explored a potential cell of origin in PDS and validated our findings using publicly available single-cell sequencing data. By correlating tumor purity (TP), inferred by both RNA- and DNA-sequencing, to protein abundance, we found that fibroblasts shared most of the proteins correlating to TP. This observation could also be made using publicly available SNT single cell sequencing data. Moreover, we studied relevant pathways of receptor/ligand (R/L) interactions. Analysis of R/L interactions revealed distinct pathways in cSCC, MM and PDS, with a prominent role of PDGFRB-PDGFD R/L interactions and upregulation of PI3K/AKT signaling pathway. By studying differentially expressed proteins between cSCC and PDS, markers such as MAP1B could differentiate between these two entities. To this end, we studied proteins associated with immunosuppression in PDS, uncovering that immunologically cold PDS cases shared a “negative regulation of interferon-gamma signaling” according to overrepresentation analysis.

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

Cited by 6 publications

References 56 publications

Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs

Galectin-7 reprograms skin carcinogenesis by fostering innate immune evasive programs

Squamous cell carcinoma‐derived G‐CSF promotes tumor growth and metastasis in mice through neutrophil recruitment and tumor cell proliferation, associated with poor prognosis of the patients

Proteomic analysis of pleomorphic dermal sarcoma reveals a fibroblastic cell of origin and distinct immune evasion mechanisms

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