Tumor-extrinsic discoidin domain receptor 1 promotes mammary tumor growth by regulating adipose stromal interleukin 6 production in mice

Huai-Chin Chiang,Xiujie Sun,Rong Li,Deyi Zhang,Kshama Gupta,Yanfen Hu,Tyler J. Curiel,Bogang Wu,Michelle P. Bendeck,Bin Yuan,Stephen Hursting,Xiaowen Zhang,Chi Zhang

doi:10.1074/jbc.ra117.000672

Abstract

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. SVF-produced 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.

Highlights

Discoidin domain receptor 1 (DDR1) is a collagen receptor that mediates cell communication with the extracellular matrix (ECM)
Using genetically engineered mice and syngeneic tumor models, we demonstrate the importance of host DDR1 in tumor growth, significantly extending the current understanding of the DDR1 tumor-promoting function
We further show that DDR1 in adipose tissuederived stromal–vascular fraction (SVF) is a previously unappreciated regulator of stromal interleukin 6 (IL-6) secretion that affects tumor cell migration and invasion

Summary

Introduction

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. 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. It is increasingly evident that, in addition to mature adipocytes, altered abundance and properties of human adipose stem/stromal cells (ASCs) and elevated fibrosis contribute to tissue remodeling associated with tumor-associated adipose tissue (2, 10 –12). DDR1 is predominantly expressed in normal epithelial cells, and its aberrant expression is associated with multiple solid cancer types. For these reasons, the current literature on DDR1 function in cancer biology has exclusively been focused on its activity in tumor cells (20 –22). Comparative gene expression profiling shows that stromal DDR1 expression in invasive breast cancer is significantly elevated versus normal breast stroma [23] (6.4-fold, p ϭ 1 ϫ 10Ϫ15), suggesting a possible DDR1 function in stromal cells during cancer progression

Methods

Results

Conclusion