Transcriptome Analysis Identifies Tumor Immune Microenvironment Signaling Networks Supporting Metastatic
Lawrence P McKinney1, Rajesh Singh1, I King Jordan2
1Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, GA 30310, USA.
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.
Insights
Researchers identified key genes and pathways linked to bone metastasis in lethal prostate cancer. This discovery offers new insights into the molecular mechanisms driving prostate cancer spread to bones.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in men.
- Metastatic castration-resistant prostate cancer (mCRPC) is the most lethal form, with bone metastasis being a critical factor.
- The molecular mechanisms driving mCRPC bone metastasis are not fully understood.
Purpose of the Study:
- To identify gene expression patterns and molecular mechanisms associated with mCRPC bone metastasis.
- To pinpoint key genes and biological pathways involved in the progression of mCRPC to bone.
Main Methods:
- RNA sequencing data from 60 mCRPC patients were analyzed.
- Weighted Gene Co-expression Network Analysis (WGCNA) was employed to identify gene modules correlated with bone metastasis.
- Upstream regulator analysis, Gene Ontology (GO), and KEGG enrichment analyses were performed.
Main Results:
- A specific gene cluster, the cyan module (M14), showed a strong positive correlation with mCRPC bone metastasis (r=0.81, p=4x10^-15).
- This module was significantly associated with parathyroid hormone synthesis, secretion, and action, and protein digestion and absorption pathways.
- Ten hub genes, including ALPL, PHEX, RUNX2, and collagen genes (COL11A1, COL24A1, COL22A1, COL13A1), were identified as critical players.
Conclusions:
- The study identified key molecular pathways and genes, particularly within the cyan module, that are significantly associated with bone metastasis in mCRPC.
- These findings provide novel insights into the pathogenesis of mCRPC bone metastasis and suggest potential therapeutic targets.
