Hypoxia takes invadopodia up a Notch

Díaz et al. describe how several signaling pathways combine to enhance cancer cells’ invasive capabilities.

Cancer cells form actin-rich protrusions called invadopodia, which degrade the extracellular matrix and potentially allow tumors to invade surrounding tissue. Tumor cells are often deprived of oxygen, and hypoxia can promote invadopodia formation in vitro. But how this pathway is regulated is unclear.

Díaz et al. found that the transcription factor HIF-1α, which is stabilized in low oxygen conditions, was required for hypoxia-induced invadopodia formation. Hypoxia and HIF-1α are known to activate Notch signaling, another pathway that promotes cancer cell invasion. Blocking Notch activation prevented hypoxia from inducing invadopodia.

But how does Notch signaling promote invadopodia formation? Díaz et al. found that hypoxia and Notch activation boosted the level of ADAM12, a metalloprotease that sheds growth factors from the outer surface of cells. Conditioned medium collected from control hypoxic cells—but not from cells lacking ADAM12—could induce invadopodia in oxygen-rich cells, indicating that ADAM12 releases an invadopodia-promoting factor from oxygen-deficient cancer cells. That factor turned out to be HB-EGF, a soluble ligand for the EGF receptor.

Because Notch signaling is dependent on cell contact and HB-EGF is a paracrine signaling molecule, hypoxic cancer cells may therefore induce invadopodia in both neighboring and distant tumor cells, coordinating their collective invasion. ADAM12 was up-regulated in hypoxic regions of lung tumors, suggesting that this pathway may also operate in vivo, a possibility that lead author Begoña Díaz now wants to investigate.