Collagen Deposition-Promoting Gene Linked to Cancer Metastasis

Cancer researchers have identified a gene that when active promotes the metastasis of breast cancer (BC) by increasing collagen deposition by breast cancer-associated mesenchymal stem/multipotent stromal cells.

The molecular mechanism underlying the increased collagen disposition was not known. To correct this deficiency, investigators at the University of Michigan analyzed the activity of the collagen receptor discoidin domain receptor 2 (DDR2) gene, which is essential for stromal-BC communication. They looked at levels of ddr2 enzyme activity in cells at sites of BC metastasis as well as working with the slie line of mice, which had been genetically engineered to lack the DDR2 gene.

The investigators reported in the January 31, 2017, issue of the journal Cell Reports that in human BC metastasis, DDR2 was consistently upregulated in metastatic cancer cells and in multipotent mesenchymal stromal cells (MSCs). In MSCs isolated from human BC metastasis, DDR2 maintained a fibroblastic phenotype with collagen deposition and induced pathological activation of DDR2 signaling in BC cells.

Loss of DDR2 in MSCs impaired their ability to promote DDR2 phosphorylation in BC cells, as well as BC cell alignment, migration, and metastasis. Female ddr2-deficient mice homozygous for the slie mutation showed inefficient spontaneous BC metastasis.

“We discovered that DDR2 mediates the communication between mesenchymal stem cells and cancer cells,” said senior author Dr. Celina Kleer, professor of pathology at the University of Michigan. “When we inhibit this receptor in the mesenchymal stem cells, it tricks the cancer cells. The cells do not align, they do not migrate, and they do not metastasize efficiently. This suggests a possible therapeutic target. Our goal is to identify a way to interrupt breast cancer metastasis growth and invasiveness, either to prevent metastases from forming or to keep them at bay when they do develop. The microenvironment is a rich opportunity to better understand why cancer metastasizes and begin to attack that process.”