Outgrowth of single oncogene-expressing cells from suppressive epithelial environments.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Clonal Evolution* ; Gene Expression Regulation, Neoplastic*; Cell Transformation, Neoplastic/*genetics ; Cellular Microenvironment/*physiology ; Epithelial Cells/*metabolism ; Epithelial Cells/*pathology ; Oncogenes/*genetics; Acinar Cells/cytology ; Acinar Cells/metabolism ; Acinar Cells/pathology ; Cell Adhesion ; Cell Culture Techniques ; Cell Line ; Cell Movement ; Cell Proliferation ; Cell Transformation, Neoplastic/pathology ; Cells, Cultured ; Contact Inhibition ; Epithelial Cells/cytology ; Receptor, ErbB-2/genetics ; Receptor, ErbB-2/metabolism ; Tumor Microenvironment

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.

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P01 CA080111 United States CA NCI NIH HHS; R01 CA105134 United States CA NCI NIH HHS; R01 CA105134-09 United States CA NCI NIH HHS; CA080111 United States CA NCI NIH HHS

EC 2.7.10.1 (Receptor, ErbB-2)

Date Created: 20120210 Date Completed: 20120326 Latest Revision: 20211021

20240628

PMC3297969

10.1038/nature10826

22318515