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Outgrowth of single oncogene-expressing cells from suppressive epithelial environments.
Nature.Feb 08, 2012;482(7385):410-3.
Leung CT, Brugge JS.
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Tumorigenesis is a clonal evolution process that is initiated from single cells within otherwise histologically normal tissue. It is unclear how single, sporadic mutant cells that have sustained oncogenic alterations evolve within a tightly regulated tissue environment. Here we investigated the effects of inducing oncogene expression in single cells in organotypic mammary acini as a model to elucidate the processes by which oncogenic alterations initiate clonal progression from organized epithelial environments. Sporadic cells induced to overexpress oncogenes that specifically perturb cell-cycle checkpoints (for example, E7 from human papilloma virus 16, and cyclin D1), deregulate Myc transcription or activate AKT signalling remained quiescent within growth-arrested acini. By contrast, single cells that overexpress ERBB2 initiated a cellular cascade involving cell translocation from the epithelial layer, as well as luminal outgrowth that is characteristic of neoplastic progression in early-stage epithelial tumours. In addition, ERBB2-mediated cell translocation to the lumen was found to depend on extracellular-regulated kinase and matrix metalloproteinase activities, and genetic alterations that perturb local cell-matrix adhesion drove cell translocation. We also provide evidence that luminal cell translocation may drive clonal selection by promoting either the death or the expansion of quiescent oncogene-expressing cells, depending on whether the pre-existing alterations allow anchorage-independent survival and growth. Our data show that the initial outgrowth of single oncogene-expressing cells from organized epithelial structures is a highly regulated process, and we propose that a cell translocation mechanism allows sporadic mutant cells to evade suppressive micro-environments and elicits clonal selection for survival and proliferative expansion outside the native niches of these cells.