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STC1 competitively binding βPIX enhances melanoma progression via YAP nuclear translocation and M2 macrophage

Zhaozhou Ren1, Zhijie Xu1, Xiyue Chang1

  • 1Department of Orthopedics, Shengjing Hospital of China Medical University, 36 Sanhao Street, Heping District, Shenyang, Liaoning 110004, China.

Pharmacological Research
|May 20, 2024
PubMed

Insights

Stanniocalcin-1 (STC1) promotes melanoma lung metastasis by enhancing M2 macrophage recruitment and immune evasion. Targeting STC1 may improve immunotherapy effectiveness against melanoma.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Melanoma progression involves metastasis, angiogenesis, and immune evasion.
  • Stanniocalcin-1 (STC1) is implicated in various cancers, but its role in melanoma is not fully understood.
  • Tumor-associated macrophages (TAMs), particularly M2 polarized, contribute to an immunosuppressive microenvironment and metastasis.

Purpose of the Study:

  • To investigate the role of STC1 in melanoma progression, focusing on metastasis, angiogenesis, and immune evasion.
  • To elucidate the molecular mechanisms underlying STC1's function in melanoma.
  • To evaluate STC1 as a potential therapeutic target for melanoma and its combination with immunotherapy.

Main Methods:

  • Bioinformatics analysis to assess STC1's correlation with prognosis and immune infiltration.
  • In vitro assays (A375 cells) for proliferation, invasion, migration, and angiogenesis.
  • In vivo lung metastasis model (B16-F10 cells in mice) to study macrophage infiltration and polarization.
  • Co-culture systems to analyze melanoma-macrophage crosstalk.
  • Molecular techniques including mass spectrometry, Co-IP, Dual-Luciferase Reporter Assay, and ChIP to investigate STC1, YAP, βPIX, and CCL2 interactions.

Main Results:

  • STC1 promotes lung metastasis by recruiting and polarizing M2 macrophages, creating an immunosuppressive environment.
  • STC1 activates YAP by competing with it for βPIX binding, leading to CCL2 upregulation.
  • CCL2 induces M2 macrophages to secrete VEGFA, promoting vascularization and STC1 expression in melanoma cells, forming a pro-metastatic loop.
  • STC1-induced YAP activation upregulates PD-L1, contributing to immune evasion.
  • Silencing STC1 enhances the efficacy of PD-1 immune checkpoint therapy in vivo.

Conclusions:

  • STC1 is a key driver of melanoma lung metastasis and immune evasion.
  • STC1 orchestrates a complex crosstalk with M2 macrophages, promoting a pro-metastatic and immunosuppressive tumor microenvironment.
  • STC1 represents a promising therapeutic target for inhibiting melanoma metastasis and enhancing the effectiveness of PD-1 immunotherapy.
Keywords:
STC1YAPfeedback loopmacrophagesmelanomaβPIX

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