TY - JOUR
T1 - Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice
AU - Sun, Xiujie
AU - Gupta, Kshama
AU - Wu, Bogang
AU - Zhang, Deyi
AU - Yuan, Bin
AU - Zhang, Xiaowen
AU - Chiang, Huai Chin
AU - Zhang, Chi
AU - Curiel, Tyler J.
AU - Bendeck, Michelle P.
AU - Hursting, Stephen
AU - Hu, Yanfen
AU - Li, Rong
N1 - Funding Information:
This work was supported by NCI, National Institutes of Health Grants CA206529 and CA161349, Department of Defense Grant WSlXWH-14-1-0129), and the Tom C. and H. Frost Endowment (to R. L.); NCI, National Institutes of Health Grant CA212674, Department of Defense Grant W81XWH-17-1-0007, and Cancer Prevention and Research Institute of Texas Grant RP170126 (to Y.-F. H.); National Institutes of Health Postdoc-toral Training Grant T32CA148724 (to H.-C. C.); and the Owens Foundation and the Skinner Endowment (to T. J. C.). This work was also supported by University of Texas Health San Antonio Cancer Center Grant CA054174. The authors declare that they have no conflicts of interest with the con-tents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Insti-tutes of Health.
Publisher Copyright:
© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2018/2/23
Y1 - 2018/2/23
N2 - Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1-KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVFproduced IL-6 is important for SVF-stimulated tumor cell invasion in vitro, and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth.
AB - Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM). Aberrant expression and activity of DDR1 in tumor cells are known to promote tumor growth. Although elevated DDR1 levels in the stroma of breast tumors are associated with poor patient outcome, a causal role for tumor-extrinsic DDR1 in cancer promotion remains unclear. Here we report that murine mammary tumor cells transplanted to syngeneic recipient mice in which Ddr1 has been knocked out (KO) grow less robustly than in WT mice. We also found that the tumor-associated stroma in Ddr1-KO mice exhibits reduced collagen deposition compared with the WT controls, supporting a role for stromal DDR1 in ECM remodeling of the tumor microenvironment. Furthermore, the stromal-vascular fraction (SVF) of Ddr1 knockout adipose tissue, which contains committed adipose stem/progenitor cells and preadipocytes, was impaired in its ability to stimulate tumor cell migration and invasion. Cytokine array-based screening identified interleukin 6 (IL-6) as a cytokine secreted by the SVF in a DDR1-dependent manner. SVFproduced IL-6 is important for SVF-stimulated tumor cell invasion in vitro, and, using antibody-based neutralization, we show that tumor promotion by IL-6 in vivo requires DDR1. In conclusion, our work demonstrates a previously unrecognized function of DDR1 in promoting tumor growth.
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U2 - 10.1074/jbc.RA117.000672
DO - 10.1074/jbc.RA117.000672
M3 - Article
C2 - 29298894
AN - SCOPUS:85042352826
VL - 293
SP - 2841
EP - 2849
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 8
ER -