Dynamic prostate cancer transcriptome analysis delineates the trajectory to disease progression.

Area of Science:

• Oncology
• Genomics
• Transcriptomics

Background:

• Genomic studies identify cancer driver mutations, but transcriptional changes are often unclear due to data biases.
• Understanding cancer progression requires a detailed view of gene expression dynamics.

Purpose of the Study:

• To create a comprehensive prostate cancer transcriptome atlas detailing tumor progression.
• To elucidate the transcriptional roadmap and mechanisms driving cancer progression.

Main Methods:

• Developed a prostate cancer transcriptome atlas.
• Utilized patient-derived xenograft models with single-cell resolution.
• Analyzed transcriptional changes and validated findings functionally.

Main Results:

• Identified a uniform cancer progression trajectory involving polycomb-repressive-complex-2, G2-M checkpoints, and M2 macrophage polarization.
• Demonstrated tumor progression via transcriptional adaptation, not selection of cell clusters.
• Showed EZH2 inhibition reverses tumor progression and macrophage polarization at the single-cell level.

Conclusions:

• Prostate cancer progression follows a predictable transcriptional path.
• Transcriptional adaptation is a key driver of tumor progression.
• EZH2 inhibition presents a potential therapeutic strategy for reversing cancer progression and associated immune changes.