DDR1 key for cancer cell escape

Juin et al. identify the receptor that allows cancer cells to recognize and break through type I collagen.

Type I collagen is prevalent in many tumors. But in contrast to what researchers long thought, it does not corral cancer cells. Instead, cancer cells grow actin-containing extensions called invadosomes that break down collagen and allow the cells to slip through. Although invadosomes—the term encompasses the invadopodia of cancer cells and the protrusions of healthy cells—form in a variety of situations, type I collagen induces cancer cells to produce linear invadosomes that orient along collagen fibers. To their surprise, the researchers previously found that integrins, the main collagen receptors, aren’t involved in formation of this type of invadosome.

Juin et al. determined that Discoidin Domain Receptor 1 (DDR1), a protein overexpressed in many cancers, senses type I collagen and induces the formation of linear invadosomes. When the researchers knocked down DDR1, cells were unable to infiltrate a 3D collagen gel, suggesting that the protein is important for metastasis.

Although DDR1 is a tyrosine kinase, blocking its kinase activity didn’t inhibit linear invadosomes. The invadosome inducer Src had no role in their growth either. The researchers found that DDR1 indirectly activated the guanine nucleotide exchange factor Tuba, which then switched on Cdc42. In turn, Cdc42 promoted actin polymerization and spurred invadosomes to grow. The results suggest that blocking DDR1’s ability to induce linear invadosomes might curtail metastasis.