Normal cells require attachment to the extracellular matrix (ECM) to survive, and ECM detachment causes metabolic impairments (such as reduced ATP levels), largely through a reduction in nutrient uptake owing to decreased phosphoinositide 3-kinase signalling. Grassian et al. now delineate alterations in metabolic pathways associated with ECM detachment and show that there is also a reduction in flux through pyruvate dehydrogenase (PDH) as a result of diminished extracellular signal-related kinase (ERK) pathway signalling, revealing an unanticipated function for ERK in the regulation of metabolism.

The authors used metabolic flux analysis to examine global cellular metabolism, comparing the metabolic activity of the non-tumorigenic cell line MCF-10A in detached and attached growth conditions. As ERBB2 overexpression is known to rescue cell survival in detached conditions, Grassian et al. also used an MCF-10A ERBB2-overexpressing cell line. They found that ECM detachment led to a decrease in metabolic flux through glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA) cycle; these effects were, however, rescued by ERBB2.

an unanticipated function for ERK in the regulation of metabolism.

In particular, they noticed that, when ERBB2 was not overexpressed, ECM detachment reduced flux through PDH, which is a key regulator of TCA cycle activity, as it converts pyruvate to the main substrate for the TCA cycle, acetyl CoA. PDH flux is regulated by the inhibitory kinases PDH kinase 1 (PDK1)–PDK4. They found that there was an increase specifically in PDK4 mRNA following ECM detachment, and this increase was reduced in ERBB2-overexpressing cells. PDK4 is known to inhibit PDH through phosphorylation on Ser293; detachment from the ECM caused increased phosphorylation of PDH at this site in normal cells but not in ERBB2-overexpressing cells.

The TCA cycle supplies biosynthetic intermediates for various cellular processes. The authors found that PDK4 overexpression caused a decrease in de novo lipogenesis and cell proliferation; thus, PDK4-mediated inhibition of PDH flux may contribute to the metabolic impairments seen in ECM-detached cells. But, how does detachment from the ECM lead to PDK4 inhibition, and why is this not observed in ERBB2-overexpressing cells? As ERBB2 is known to maintain ERK signalling in ECM-detached cells, the authors pharmacologically inhibited ERK pathway components. They found that this caused increased PDK4 levels in detached cells, decreased PDH flux and similar metabolic changes to those observed in ECM-detached cells.

Taken together, the data suggest that ECM attachment and ERBB2 increase PDH flux by suppressing PDK4 expression and that this is mediated by ERK signalling. PDK4 mRNA is commonly downregulated in human cancers compared with the tissue of origin; thus, the oncogenic function of ERBB2 may involve inhibiting PDK4, allowing cancerous cells to detach from the ECM without suffering the metabolic defects that occur in normal cells.