Granulin+ Macrophages Promote Lineage Plasticity in Prostate Cancer Through Paracrine Signaling Loops

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Lineage plasticity is a known cause of prostate cancer therapy resistance.
• The role of tumor-infiltrating immune cells in this phenotype switching is not well understood.

Purpose of the Study:

• To characterize immune infiltration, transcriptional changes, and cell communication in prostate cancer progression.
• To identify mechanisms driving therapy resistance through lineage plasticity.

Main Methods:

• Single-cell multi-omics analysis of prostate cancer progression.
• Functional validation using in vitro models and patient-derived organoids.
• Therapeutic intervention studies in mouse models (TRAMP).

Main Results:

• Granulin (GRN)-expressing macrophages promote adenocarcinoma to therapy-resistant multilineage state transition via GRN/TNFRSF1A and NF-κB pathway.
• A feedforward loop involving CSF1/CSF1R sustains lineage plasticity.
• GRN drives epithelial-mesenchymal transition and enzalutamide resistance.
• CSF1R inhibition reduces GRN+ macrophages and suppresses multilineage subclone emergence.
• Identified novel stromal populations linked to disease relapse.

Conclusions:

• GRN+ macrophages are key mediators of lineage plasticity and therapy resistance in prostate cancer.
• The GRN/CSF1R axis represents a promising therapeutic target.
• Understanding tumor-immune crosstalk is crucial for overcoming advanced prostate cancer resistance.