Major finding: Cell translocation can promote escape from suppressive tissue environments.
Approach: Growth-arrested acini were infected with low-dose lentiviral vectors harboring oncogenes.
Impact: Tracking single mutant cells provides insight into the early steps of epithelial tumor evolution.
The evolution of a single cell that has acquired a sporadic oncogenic mutation into a tumor requires clonal outgrowth and selection in an otherwise normal microenvironment poised to eliminate aberrant cells. To study this process, Leung and Brugge infected growth-arrested 3-dimensional mammary epithelium cell cultures with low-dose lentiviral vectors expressing GFP and various oncogenes so that the outcome of oncogene expression in single cells could be tracked within a “mature,” tissue-like acinar structure. This approach revealed that most individual oncogene-expressing cells remained quiescent in the epithelial layer. However, overexpression of ERBB2 (HER2), which is amplified in 30% of breast cancers, was sufficient for luminal outgrowth. ERBB2 induced luminal translocation that was dependent on ERK signaling and matrix metalloproteinase (MMP) activation, both of which also were sufficient to induce migration into the lumen. Forced translocation of quiescent oncogene-expressing cells by MMP coexpression showed that translocation promoted clonal outgrowth only in mutants that could survive in the matrix-deprived lumen. Additionally, destabilization of epithelial cell–cell junctions via p120-catenin knockdown generally increased proliferation in all mutants tested, although the capacity for luminal translocation was not affected. These data indicate that the mature epithelium creates a suppressive environment in which cells that have acquired a single oncogenic mutation usually remain dormant, but local perturbations of cell-matrix contacts and intrinsic cellular ERK and MMP activity may facilitate evasion of epithelial constraints and initiate epithelial tumor evolution by inducing the clonal expansion and luminal translocation of cells with oncogenic mutations.
Leung CT, Brugge JS. Outgrowth of single oncogene-expressing cells from suppressive epithelial environments. Nature 2012 Feb 8. [Epub ahead of print].
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