A protein that promotes the spread of breast cancer cells has been identified by a new study from researchers at the University of Michigan Comprehensive Cancer Center. DDR2 is part of a well-known family of receptors, tyrosine kinase receptors, which are implicated in many types of cancer and for which promising inhibitors are being developed.

To better understand what makes breast cancer spread, scientists are looking at where it lives, not just its original home in the breast but its new home where it settles in other organs. They are asking what’s happening in that metastatic niche where migrated cancer cells are growing.

Celina Kleer, M.D., Harold A. Oberman Collegiate Professor of Pathology at Michigan Medicine, says:

“A role for the tumor microenvironment in metastasis is being unraveled. If we can understand these mechanisms, we can find ways to inhibit them and prevent metastasis."

Improving Survival

In roughly 20 percent of patients breast cancer metastasizes, or spreads, to distant sites in the body. Researchers hope that stopping this spread or neutralizing its impact once it does spread will improve survival.

Kleer and her colleagues took tissue samples from patients, directly from the metastatic breast cancer lesions, to study the cells surrounding the area where these migrated tumors had set up. There are a whole host of cells in the cancer microenvironment, including immune cells, vasculature and mesenchymal stem cells.

The researchers found in particular that activity in the mesenchymal stem cells — progenitor cells shown to nurture tumor growth — influenced metastasis.

The team found DDR2, a collagen receptor tyrosine kinase, is like the Pied Piper. It paves the road, coaxing breast cancer cells to spread, and stimulates signaling to increase cancer cell growth.

When DDR2 was present in cells, the researchers could see an orderly and efficient migration in which cancer cells, mesenchymal stem cells and collagen neatly align to form a metastasis. When DDR2 was deleted from cells, the cancer cells and collagen were in disarray, which led to less migration and fewer metastases.

Mesenchymal Stem Cells And Cancer Cells

Researchers then studied mice in which DDR2 was deficient. Those mice formed fewer metastases and showed no signs of the orderly alignment of cells.

“We discovered that DDR2 mediates the communication between mesenchymal stem cells and cancer cells,” says Kleer. “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."

While an inhibitor of DDR2 is not available, inhibitors have been developed against other tyrosine kinases, such as HER2 and EGFR, suggesting that DDR2 is a well-suited target for drug development.

“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,” Kleer says.

The researchers are continuing to study what happens when DDR2 is activated in breast cancer cells and how it promotes metastases.

Maria E. Gonzalez et al Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth Cell Reports (2017). DOI: 10.1016/j.celrep.2016.12.079

Image: Immunofluorescence image showing breast cancer cells (green) aligned with mesenchymal stem cells (red) expressing DDR2 protein (white). Credit: Michigan Medicine

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