Single-cell analysis reveals a stem-cell program in @entity1 metastatic XXXX cells.

@entity1 @entity0 @entity5 @entity19 @entity3
UNASSIGNED: Despite major advances in understanding the molecular and genetic basis of @entity5 , @entity3 remains the cause of >90% of @entity5 -related mortality. Understanding @entity3 initiation and progression is critical to developing new therapeutic strategies to treat and prevent @entity3 . Prevailing theories hypothesize that @entity3 are seeded by rare @entity5 cells with unique properties, which may function like stem cells in their ability to initiate and propagate @entity5 . However, the identity of @entity3 -initiating cells in @entity1 @entity0 remains elusive, and whether @entity3 are hierarchically organized is unknown. Here we show at the single-cell level that early stage metastatic cells possess a distinct stem-like gene expression signature. To identify and isolate metastatic cells from @entity1 -derived xenograft models of @entity1 @entity0 , we developed a highly sensitive fluorescence-activated cell sorting (FACS)-based assay, which allowed us to enumerate metastatic cells in @entity19 peripheral tissues. We compared gene signatures in metastatic cells from tissues with low versus high metastatic burden. Metastatic cells from low-burden tissues were distinct owing to their increased expression of stem cell, epithelial-to-mesenchymal transition, pro-survival, and dormancy-associated genes. By contrast, metastatic cells from high-burden tissues were similar to primary @entity5 cells, which were more heterogeneous and expressed higher levels of luminal differentiation genes. Transplantation of stem-like metastatic cells from low-burden tissues showed that they have considerable @entity5 -initiating capacity, and can differentiate to produce luminal-like @entity5 cells. Progression to high metastatic burden was associated with increased proliferation and MYC expression, which could be attenuated by treatment with cyclin-dependent kinase (CDK) inhibitors. These findings support a hierarchical model for @entity3 , in which @entity3 are initiated by stem-like cells that proliferate and differentiate to produce advanced @entity3 .
