Credit: S. Bradbrook/Springer Nature Limited

Matrix metalloproteinases (MMPs) degrade the basement membrane — a dense extracellular matrix that surrounds all tissues, thereby facilitating cell invasion. Kelley et al. now reveal a compensatory mechanism of cell invasion in the absence of MMPs, relying on increased polymerization of branched actin.

To study cell invasion in vivo, the authors used Caenorhabditis elegans anchor cells, which are specialized uterine cells that invade through the basement membrane into the underlying vulval epithelium during worm development. They generated mutants of five MMPs that localize at the site of anchor cell invasion. Interestingly, even in the absence of all five MMPs (MMP–), anchor cell invasion persisted, although it was delayed by ~1 h; this was associated with the generation of large protrusions — in place of small invadopodia characteristic of wild-type cells — and pronounced physical displacement of basement membrane components away from the invasion site, rather than basement membrane degradation. Thus, anchor cells adapt to the loss of MMPs and efficiently invade the tissue by physically breaching the basement membrane.

Branched actin networks generated by the Arp2/3 complex were previously implicated in anchor cell invasion. Removal of an Arp2/3 subunit by RNAi nearly completely blocked invasion of MMP– cells. In addition, Arp2/3 and F-actin were enriched at the invasive front in MMP– cells compared with wild-type cells. Thus, increased formation of branched actin networks driven by Arp2/3 supports anchor cell invasion in the absence of MMPs.

A genome-wide synthetic RNAi screen further identified the mitochondrial ATP/ADP translocase ANT1.1 as a factor promoting MMP-independent invasion of anchor cells. Accordingly, mitochondria were enriched at the invasive front in MMP– cells, where they were tightly associated with F-actin. ATP production was also increased at the invasive front of MMP– cells, suggesting that enhanced ATP production at the invasive front supports increased branched actin assembly and MMP-independent invasion.

anchor cells … efficiently invade the tissue by physically breaching the basement membrane

Thus, MMPs are not absolutely required for cell invasion in vivo — in the absence of MMPs cells can physically breach basement membrane barriers using large protrusions enriched in branched actin and ATP-generating mitochondria. These findings may explain the failure of MMP inhibitors as cancer therapeutics and could inform new approaches to block cancer metastasis.