Uncovering phenotypic heterogeneity through research autopsy in lethal prostate cancer

Abstract

Tumor heterogeneity in metastatic prostate cancer (mPC) is well established, but comprehensive characterization using routine sampling remains challenging. Autopsy-based research addresses this obstacle by enabling broad tissue collection within individual patients after treatment. In this issue of the JCI, Roudier et al. analyzed samples from a mPC research autopsy cohort, revealing extensive inter- and intratumor heterogeneity across patients and at the cellular level. The authors associated this variability with genomic, phenotypic, and clinical features and explored the importance of tumors expressing both androgen receptor and neuroendocrine markers. Their findings demonstrate heterogeneity across metastatic sites that may influence treatment response and clinical outcomes, informing future therapeutic strategies in mPC.

Figure 1. Metastatic PC shows phenotypic heterogeneity.

Treated metastatic PC cells show genomic gains and/or losses that associate with molecular changes and result in phenotypic differentiation. The four phenotypic categories — AR⁺/NE^–, AR^–/NE^–, AR^–/NE⁺, and AR⁺/NE⁺ — are associated with differences in androgen dependence, proliferative capacity (as seen by Ki-67 expression), and metastatic locations.