Dynamics of Tumor Heterogeneity from Primary to Metastatic Dissemination in Prostate Cancer

Identifying drivers of cancer progression to guide treatment selection is hindered by limited abilities to understand tumor heterogeneity’s impact on evolution. Here, we delineated the phenotypic variability across ~300,000 prostate tumor cells collected from multi-loci in primary and matched locoregional metastases. We found inter-patient heterogeneity to be confined to malignant populations. While malignant populations exhibit intra-locus heterogeneity, they maintain inter-loci phenotypic similarity within a patient’s prostate gland. Furthermore, the inter-loci malignant population similarity is paired with a shared clonal architecture. Lastly, we show that malignant populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity observed across primary tumor loci while showcasing cell state transition to inflammatory phenotypes. These findings provide insights into four distinct measures of tumor heterogeneity, revealing diverse evolutionary paths across patients converging to common phenotypic adaptations in early prostate cancer progression.