Prostate cancer cells converge to an inflammatory-like state upon metastatic dissemination

Identifying drivers of cancer progression to guide treatment selection is hindered by our limited understanding of tumor heterogeneity and its impact on tumor evolution. Here, we delineate the phenotypic variability across ~300,000 cells collected from multiple tumor loci in primary prostate and matched locoregional metastases using single-cell chromatin accessibility and gene expression sequencing. We find inter-patient heterogeneity to be confined to malignant populations. Within individual tumor loci, we see phenotypic heterogeneity among malignant cell populations despite a shared clonal genotypic architecture. We also observe that malignant cell populations disseminating to locoregional lymph nodes mirror the clonal architecture and phenotypic heterogeneity across primary tumor loci, while shifting from canonical prostate-cancer states to non-canonical inflammatory-like states. Our findings suggest a bottleneck imposed during the dissemination process, funneling prostate cancer cells toward an inflammatory-like cell state. These insights into the interplay between phenotypic identity and clonal architecture refine our understanding of prostate cancer progression and suggest that convergence of cancer cells towards an inflammatory-like state underlies dissemination to lymph nodes, offering a critical framework for future studies into prostate cancer metastatic potential. Understanding tumor heterogeneity and its impact on prostate cancer progression remains elusive. Here, single nucleus snATAC and snRNA sequencing of a multi-loci sampled cohort of advanced prostate cancer patients identifies an inflammatory-like state underlying metastatic dissemination to the lymph nodes.