Metastases account for the great majority of cancer-associated deaths, yet this complex process remains the least understood aspect of cancer biology. As the body of research concerning metastasis continues to grow at a rapid rate, the biological programs that underlie the dissemination and metastatic outgrowth of cancer cells are beginning to come into view. In this review we summarize the cellular and molecular mechanisms involved in metastasis, with a focus on carcinomas where the most is known, and highlight the general principles of metastasis that have begun to emerge.

Single-cell RNA-sequencing technologies suffer from many sources of technical noise, including under-sampling of mRNA molecules, often termed ‘dropout’, which can severely obscure important gene-gene relationships. To address this, we developed MAGIC (Markov Affinity-based Graph Imputation of Cells), a method that shares information across similar cells, via data diffusion, to denoise the cell count matrix and fill in missing transcripts. We validate MAGIC on several biological systems and find it effective at recovering gene-gene relationships and additional structures. MAGIC reveals a phenotypic continuum, with the majority of cells residing in intermediate states that display stem-like signatures and uncovers known and previously uncharacterized regulatory interactions, demonstrating that our approach can successfully uncover regulatory relations without perturbations.

Since their identification in 1994, cancer stem cells (CSCs) have been objects of intensive study. Their properties and mechanisms of formation have together become a major focus of current cancer research, in part because of their enhanced ability to initiate and fuel tumor growth and their intrinsic resistance to conventional therapeutics. The discovery that activation in carcinoma cells of the epithelial-to-mesenchymal transition (EMT) program can give rise to cells with stem-like properties has provided one possible mechanism explaining how CSCs arise and presented a possible avenue for their therapeutic manipulation. This review addresses the more recent developments in CSC research, focusing on carcinomas that are able to undergo an EMT. We discuss the signaling pathways that create these cells, cell-intrinsic mechanisms that could be exploited for their selective elimination or induction of their differentiation, and the role of the tumor microenvironment in sustaining them. Finally, we propose ways to exploit our current knowledge of their complex biology to design novel therapies to eliminate them.

No abstract