Tumor cell plasticity promotes metastasis across heterogeneous tumors

Metastasis is the leading cause of cancer related deaths but research is challenged by limited access to patient material and experimental models that appropriately recapitulate tumor heterogeneity. Here, we analyze single-cell transcriptomes of matched primary tumor and metastasis from patient-derived xenograft models of breast cancer, demonstrating that primary tumor and metastatic cells show profound transcriptional differences across heterogeneous tumors. While primary tumor cells show increased metabolic activity, metastatic cells show a motility phenotype in micrometastatic lesions and increased stress response signaling throughout the metastatic progression. Additionally, we identified gene signatures that are associated with the metastatic potential and correlated with patient outcomes. Low metastatic primary tumors show increased immune-regulatory control that may prevent metastasis, whereas primary tumors with a high metastatic potential show an upregulation of epithelial-mesenchymal-plasticity (EMP). We found that EMP is a key feature of intra-tumor heterogeneity and the magnitude and abundance of EMP is associated with metastasis. We demonstrate that EMP is a dynamic continuum with intermediate cell states characterized by specific markers. These intermediate EMP markers correlated with worse patient outcomes and could serve as potential new therapy targets to block metastatic development.