Deciphering single-cell heterogeneity and cellular ecosystem dynamics during prostate cancer progression.

Area of Science:

• Oncology
• Genomics
• Cell Biology

Background:

• Prostate cancer (PC) progression involves complex cellular changes and phenotype plasticity, particularly under therapeutic pressure.
• Limited high-resolution data exists on cell phenotype evolution across PC stages.
• Understanding these dynamics is crucial for developing effective treatments.

Purpose of the Study:

• To create a comprehensive single-cell atlas of prostate cancer (PCCAT).
• To dissect the cellular landscape and identify cell types associated with PC progression and prognosis.
• To characterize cell states driving therapeutic resistance and immune suppression.

Main Methods:

• Integration of single-cell data from approximately 710,000 cells across 197 human prostate cancer samples.
• Analysis of diverse tumor stages, from pre-malignant lesions to castration-resistant disease.
• Identification of key cell types, molecular features, and spatial niches.

Main Results:

• Characterization of malignant cells with high MHC expression, low Androgen Receptor (AR) activity, and stemness, linked to enzalutamide resistance.
• Identification of lineage plasticity-like malignant cells (LPCs), neuroendocrine tumor cells, pericytes, and matrix cancer-associated fibroblasts (mCAFs) associated with adverse prognosis.
• Uncovering immune-suppressive cell states in advanced PC, including regulatory T cells, exhausted CD8+ T cells, and SPP1-expressing macrophages.
• Pinpointing a spatial niche of mCAFs and SPP1+ macrophages at the tumor boundary correlating with poor prognosis.

Conclusions:

• The Prostate Cancer Cell Atlas (PCCAT) provides a high-resolution resource for understanding PC progression.
• Specific cell states and their spatial organization are critical drivers of PC progression, resistance, and poor outcomes.
• Insights into the tumor microenvironment offer potential therapeutic targets for advanced prostate cancer.