Detachment of epithelial cells from the extracellular matrix (ECM) can induce profound changes in cellular metabolism, including decreased glucose uptake and ATP production. However, the mechanism by which ECM detachment affects metabolism is less well defined. Brugge and colleagues now provide fresh insight into how ECM detachment reduces ATP production and suggest a mechanism by which cancer cells avoid these metabolic changes (Genes Dev. 25, 1716–1733; 2011).

Acetyl-CoA is consumed by the tricarboxylic acid (TCA) cycle to produce ATP and other biosynthetic compounds. Pyruvate dehydrogenase kinases (PDKs) inhibit the conversion of pyruvate to acetyl-CoA by phosphorylating and inactivating the responsible catalyst — pyruvate dehydrogenase (PDH). The authors found that flux through the TCA cycle and ATP production was impaired in detached normal mammary epithelial cells, but not in those overexpressing the growth factor receptor ErbB2. Decreased PDH flux was ascribed to detachment-induced upregulation of PDK4 in normal cells. However, ErbB4 overexpression blocked PDK4 upregulation and restored PDH flux via Mek–Erk activaton. Indeed, Mek inhibition decreased PDH flux even in attached cells.

The authors went on to show that PDK4 overexpression blocked PDH flux in attached cells independently of ErbB2 expression, and inhibited cellular proliferation. These data show that TCA flux is exquisitely sensitive to ECM attachment, and suggest that hyperactive Mek–Erk signalling might protect cancer cells from detachment-induced changes in cellular metabolism and proliferation.