Merlin deficiency supports an immunosuppressive milieu in breast cancer

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Breast cancer remains a leading cause of mortality despite advances in detection and therapy.
• Cytoskeletal protein alterations, including Merlin (encoded by the NF2 gene), are implicated in tumor progression.
• The impact of Merlin deficiency on the breast tumor immune microenvironment is not well understood.

Purpose of the Study:

• To investigate the role of Merlin deficiency in breast cancer progression and immune microenvironment remodeling.
• To explore the potential of targeting the Hedgehog signaling pathway in Merlin-deficient breast tumors.

Main Methods:

• In vivo studies using Merlin-deficient breast cancer models.
• Analysis of tumor growth, immune cell infiltration (T regulatory cells, M2-like macrophages, M1-like macrophages).
• Pharmacological inhibition of the Hedgehog pathway using Vismodegib.

Main Results:

• Merlin deficiency led to accelerated tumor growth, enhanced epithelial-mesenchymal plasticity, and enrichment of Hedgehog signaling.
• Merlin-deficient tumors exhibited an immunosuppressive microenvironment with increased regulatory T cells and M2-like macrophages.
• Vismodegib treatment reduced tumor growth, decreased regulatory T cells and M2-like macrophages, and increased M1-like macrophages.

Conclusions:

• Merlin deficiency in breast cancer is associated with an immunosuppressive tumor microenvironment and increased tumor growth.
• Hedgehog pathway inhibition is a potential therapeutic vulnerability for Merlin-deficient basal-like, triple-negative breast cancer.
• Modulating the immune microenvironment through Hedgehog inhibition offers a promising therapeutic strategy.