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PMID: 28147276 Published · ppublish English Journal Article

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

Cell reports ·Vol. 18 ·No. 5 ·2017-00-31 ·Pages 1215-1228

Gonzalez ME, Martin EE, Anwar T, Arellano-Garcia C, Medhora N, Lama A, Chen YC, Tanager KS, Yoon E, Kidwell KM, Ge C, Franceschi RT, Kleer CG

Abstract

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.

Keywords
DDR2 EZH2 breast cancer collagen discoidin domain receptor mesenchymal stem cell metastasis microenvironment phosphorylated DDR2 tumor stroma
MeSH Terms
Animals Breast Neoplasms/metabolism,pathology Cell Line, Tumor Cell Movement/physiology Cell Proliferation/physiology Collagen/metabolism Discoidin Domain Receptor 2/metabolism Female Fibroblasts/metabolism,pathology Humans MCF-7 Cells Mesenchymal Stem Cells/metabolism Mice Mice, Inbred C57BL Neoplasm Metastasis/pathology Phosphorylation/physiology Receptors, Collagen/metabolism Signal Transduction/physiology
Chemicals
Receptors, Collagen Collagen DDR2 protein, human Discoidin Domain Receptor 2
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Gonzalez Maria E
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Martin Emily E
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Anwar Talha
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Arellano-Garcia Caroline
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Medhora Natasha
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Lama Arjun
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Chen Yu-Chih
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.
Tanager Kevin S
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
Yoon Euisik
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.
Kidwell Kelley M
School of Public Health, Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
Ge Chunxi
School of Dentistry, Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Franceschi Renny T
School of Dentistry, Department of Periodontics and Oral Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
Kleer Celina G
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.
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Article Info
Journal
Cell reports
Abbr.
Cell Rep
ISSN
2211-1247
DOI
10.1016/j.celrep.2016.12.079
Email
kleer@umich.edu
Published
2017-00-31
Pages
1215-1228
Language
English
Region
United States
NLM ID
101573691
PMCID
PMC5332146
Subset
IM
Grants
NCI NIH HHS · R01 CA125577 · United States
NCI NIH HHS · P30 CA046592 · United States
NIDCR NIH HHS · R01 DE011723 · United States
NIGMS NIH HHS · T32 GM007863 · United States
NIGMS NIH HHS · R25 GM086262 · United States
NCI NIH HHS · R01 CA107469 · United States
External Links
PubMed source DOI: 10.1016/j.celrep.2016.12.079 PMC Full Text View journal details
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