Stem cell dynamics and cellular heterogeneity across lineage subtypes of castrate-resistant prostate cancer

Area of Science:

• Oncology
• Cancer Biology
• Stem Cell Research

Background:

• Prostate cancer cells develop resistance to therapies like androgen receptor inhibition by adopting stem-like states.
• This lineage plasticity results in phenotypic heterogeneity, including transitions to neuroendocrine (NE) and amphicrine phenotypes in castrate-resistant prostate cancer (CRPC).

Purpose of the Study:

• To investigate the lineage hierarchy and molecular characteristics of CRPC subpopulations.
• To identify potential therapeutic targets within heterogeneous CRPC tumors.

Main Methods:

• Development of CRPC patient-derived organoid models preserving tumor heterogeneity.
• Lineage tracing and transcriptional analysis of CRPC subpopulations.
• Assessment of therapeutic targeting using an AURKA inhibitor.

Main Results:

• Stem/progenitor (St/Pr) cells were identified as a common source for all lineage populations.
• CRPC heterogeneity arises from distinct St/Pr subclones, with varying progeny differentiation and self-renewal capacities.
• Amphicrine CRPC subpopulations showed enrichment for signatures associated with clinical progression.
• An AURKA inhibitor specifically depleted amphicrine St/Pr cells and inhibited tumor growth.

Conclusions:

• Distinct stem cell characteristics are associated with subtype-specific CRPC.
• Targeting differentiation-competent prostate stem cells, such as with AURKA inhibitors, presents a potential therapeutic strategy for CRPC.