Editors' ChoiceCancer

Epithelial cells reject abnormal neighbors

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Sci. Signal.  09 May 2017:
Vol. 10, Issue 478, eaan5866
DOI: 10.1126/scisignal.aan5866

Normal epithelial cells induce metabolic changes in neighboring transformed cells to force them out of the epithelium.

To maintain epithelial homeostasis, cells are extruded apically from the epithelial sheet when they are damaged or dying or when the epithelium becomes too crowded. If the extruded cell has not already initiated apoptosis, the loss of attachment causes it to undergo another form of programmed cell death called anoikis. Normal epithelial cells can also force transformed cells out of the epithelium, a process called epithelial defense against cancer (EDAC), which involves the accumulation of the actin-binding protein filamin in normal cells where they contact the transformed cell and the accumulation of the actin-binding protein EPLIN (epithelial protein lost in neoplasm) in the transformed cell. Kon et al. found that an important part of EDAC is the ability of normal cells to induce metabolic changes in the transformed cells. When MDCK cells expressing the oncogenic protein H-RasV12 were cultured with normal MDCK cells, the H-RasV12-expressing cells were extruded from the epithelium, exhibited reduced mitochondrial activity, and increased their uptake of glucose, indicating a shift in their metabolism from mitochondrial oxidative phosphorylation to glycolysis, which occurs in the cytosol. This process required EPLIN and pyruvate dehydrogenase kinase 4 (PDK4), which inhibits oxidative phosphorylation, in the transformed cells and filamin in the surrounding normal cells. Reducing glycolysis by treating the cultures with a hexokinase inhibitor reduced the extrusion of transformed cells, indicating that the increase in glycolysis promoted their elimination. The key findings from the cell culture experiments were replicated in an in vivo model of mice mosaically expressing H-RasV12 in the intestinal epithelium and in intestinal organoids derived from these mice. Commentary from Coloff and Brugge addresses the apparent contradiction between the glycolytic phenotype in EDAC promoting the elimination of transformed cells and the known protumorigenic effects of a high rate of glycolysis (Warburg effect).

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