Outgrowth of single oncogene-expressing cells from suppressive epithelial environments

Cheuk T. Leung, Joan S. Brugge

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194 Scopus citations


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 tha 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.

Original languageEnglish (US)
Pages (from-to)410-413
Number of pages4
Issue number7385
StatePublished - Feb 16 2012

Bibliographical note

Funding Information:
Acknowledgements We thank S. Valastyan, T. Muranen and W. Lee for critical reading of the manuscript. We thank the members of the Brugge laboratory for comments and discussion, the Nikon Imaging Center at Harvard Medical School for providing imaging equipment and software, and the laboratory of G. Danuser for imaging software support. This work was supported by a grant from the National Cancer Institute (CA080111, to J.S.B.) and an American Cancer Society postdoctoral fellowship (C.T.L.).


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