Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth

Publication date: 31 January 2017
Source:Cell Reports, Volume 18, Issue 5
Author(s): Maria E. Gonzalez, Emily E. Martin, Talha Anwar, Caroline Arellano-Garcia, Natasha Medhora, Arjun Lama, Yu-Chih Chen, Kevin S. Tanager, Euisik Yoon, Kelley M. Kidwell, Chunxi Ge, Renny T. Franceschi, Celina G. Kleer
Increased collagen deposition by breast cancer (BC)-associated mesenchymal stem/multipotent stromal cells (MSC) promotes metastasis, but the mechanisms are unknown. Here, we report that the collagen receptor discoidin domain receptor 2 (DDR2) is essential for stromal-BC communication. In human BC metastasis, DDR2 is concordantly upregulated in metastatic cancer and multipotent mesenchymal stromal cells. In MSCs isolated from human BC metastasis, DDR2 maintains a fibroblastic phenotype with collagen deposition and induces pathological activation of DDR2 signaling in BC cells. Loss of DDR2 in MSCs impairs 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 show inefficient spontaneous BC metastasis. These results point to a role for mesenchymal stem cell DDR2 in metastasis and suggest a therapeutic approach for metastatic BC.

Graphical abstract

Teaser

By isolating human mesenchymal stem cells from breast cancer metastasis, Gonzalez et al. identify a pathway initiated by stromal DDR2, a unique receptor tyrosine kinase activated by fibrillar collagen, that mediates DDR2 activation in breast cancer cells and induces metastasis.


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