Recurrent intra-tumour heterogeneity is a hallmark of metastatic prostate cancer

The evolution from low grade to metastatic tumour is a major determinant of cancer mortality. Cancer evolution involves a complex interplay between intrinsic genetics and transcriptional alterations and the microenvironment. To define mechanisms underpinning metastatic development, we focused on metastatic castration-resistant prostate cancer (mCRPC) and employed single-cell multi-omics and whole-genome sequencing to deeply profile 34 metastatic lesions from 9 patients by rapid autopsy. We found that intra-tumour heterogeneity is an indicator of key evolutionary processes, characterised by recurrent tumour populations acting as critical functional components of the tumour ecosystem, irrespective of clonal and microenvironmental backgrounds. Unexpectedly, microenvironments only played a limited role while clonal evolution primarily promoted transcriptional noise. Intra-patient functional convergence of tumour ecosystems was observed across metastases, showing system-level selection pressures that drive the heterogeneity landscape of mCRPC. Our findings reveal functional evolutionary convergence of metastatic disease into units of intra-tumour heterogeneity, identifying critical determinants for therapeutic targeting.