Transcriptome Analysis Identifies Tumor Immune Microenvironment Signaling Networks Supporting Metastatic Castration-Resistant Prostate Cancer

TL;DR

This study identifies 10 genes linked to bone metastasis in lethal prostate cancer, offering potential new targets for diagnosis and treatment.

Contribution

The study introduces a novel combination of WGCNA and gene ontology analyses to identify new biomarkers for mCRPC bone metastasis.

Findings

14 gene clusters were identified, with one strongly correlated to mCRPC bone metastasis.

10 hub genes were found, two of which are novel and may serve as biomarkers.

Key pathways related to bone metabolism and collagen processes were linked to mCRPC progression.

Abstract

Prostate cancer (PCa) is the second most common cause of cancer death in American men. Metastatic castration-resistant prostate cancer (mCRPC) is the most lethal form of PCa and preferentially metastasizes to the bones through incompletely understood molecular mechanisms. Herein, we processed RNA sequencing data from patients with mCRPC (n = 60) and identified 14 gene clusters (modules) highly correlated with mCRPC bone metastasis. We used a novel combination of weighted gene co-expression network analysis (WGCNA) and upstream regulator and gene ontology analyses of clinically annotated transcriptomes to identify the genes. The cyan module (M14) had the strongest positive correlation (0.81, p = 4 × 10−15) with mCRPC bone metastasis. It was associated with two significant biological pathways through KEGG enrichment analysis (parathyroid hormone synthesis, secretion, and action and protein digestion and absorption). In particular, we identified 10 hub genes (ALPL, PHEX, RUNX2, ENPP1, PHOSPHO1, PTH1R, COL11A1, COL24A1, COL22A1, and COL13A1) using cytoHubba of Cytoscape. We also found high gene expression for collagen formation, degradation, absorption, cell-signaling peptides, and bone regulation processes through Gene Ontology (GO) enrichment analysis.

Metastatic castration-resistant prostate cancer (mCRPC) is potentially lethal and often spreads to the bones through a biological mechanism we do not completely understand. A previous study sequenced RNA from patients with mCRPC, and in this study, we have identified 10 genes associated with mCRPC that spread to the bones; two of those genes are novel discoveries that could serve as new biomarkers for diagnosis or molecular targets for treatment. However, future studies are required to validate these genes’ molecular role in mCRPC progression.

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