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 extrinsic microenvironment. To define the key mechanisms underpinning metastatic development, we focused on the 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 obtained through 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. 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 of metastatic progression for therapeutic targeting.