The Role of Hedgehog Signaling in the Melanoma Tumor Bone Microenvironment

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Tumor microenvironments regulate melanoma progression and treatment resistance.
• Hedgehog (Hh) signaling in the bone microenvironment is a potential therapeutic target for melanoma.
• The mechanism of melanoma-induced bone destruction via Hh/Gli signaling is not fully understood.

Purpose of the Study:

• To investigate the role of Hh/Gli signaling in melanoma-induced bone destruction.
• To evaluate the efficacy of Gli1 and Gli2 inhibition in a preclinical melanoma bone metastasis model.
• To explore the impact of Gli inhibition on tumor angiogenesis, osteoclastogenesis, and immune suppression.

Main Methods:

• Analysis of oral malignant melanoma specimens for Hh/Gli pathway components.
• Establishment of a B16 melanoma bone destruction mouse model.
• Treatment with GANT61, a small-molecule inhibitor of Gli1 and Gli2.
• Assessment of bone destruction, osteoclast activity, and tumor vasculature.
• Gene set enrichment analysis and flow cytometry for PD-L1 expression.

Main Results:

• Sonic Hedgehog, Gli1, and Gli2 were highly expressed in melanoma specimens.
• GANT61 treatment significantly inhibited cortical bone destruction, osteoclast formation, and tumor angiogenesis in vivo.
• GANT61 altered gene expression related to apoptosis, angiogenesis, and PD-L1 pathway.
• PD-L1 expression was decreased in GANT61-treated cells undergoing apoptosis.

Conclusions:

• Molecular targeting of Gli1 and Gli2 inhibits melanoma-induced bone destruction.
• Inhibition of Gli1/Gli2 may normalize tumor angiogenesis and bone remodeling in advanced melanoma.
• Targeting Gli signaling could potentially alleviate immunosuppression in the tumor bone microenvironment, offering a new therapeutic strategy for melanoma with jaw bone invasion.