Mesenchymal Stem Cell-Induced DDR2 Mediates Stromal-Breast Cancer Interactions and Metastasis Growth.
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.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Maria E
ME
Gonzalez
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Emily E
EE
Martin
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Talha
T
Anwar
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Caroline
C
Arellano-Garcia
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Natasha
N
Medhora
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Arjun
A
Lama
Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA; Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA.
Yu-Chih
YC
Chen
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Kevin S
KS
Tanager
Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Euisik
E
Yoon
School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
Kelley M
KM
Kidwell
School of Dentistry, Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Chunxi
C
Ge
School of Dentistry, Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Renny T
RT
Franceschi
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: kleer@umich.edu.
Celina G
CG
Kleer
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology*; D003094:Collagen / Q000378:metabolism; D000070820:Discoidin Domain Receptor 2 / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D061986:MCF-7 Cells; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology*; D010766:Phosphorylation / Q000502:physiology; D038981:Receptors, Collagen / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D038981:Receptors, Collagen; D003094:Collagen; C000603239:DDR2 protein, human; D000070820:Discoidin Domain Receptor 2
DDR2; EZH2; breast cancer; collagen; discoidin domain receptor; mesenchymal stem cell; metastasis; microenvironment; phosphorylated DDR2; tumor stroma