Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1

Xueqian Zhuang; Hao Zhang; Xiaoyan Li; Xiaoxun Li; Min Cong; Fangli Peng; Jingyi Yu; Xue Zhang; Qifeng Yang; Guohong Hu

doi:10.1038/ncb3613

Differential effects on lung and bone metastasis of breast cancer by Wnt signalling inhibitor DKK1

Nat Cell Biol. 2017 Oct;19(10):1274-1285. doi: 10.1038/ncb3613. Epub 2017 Sep 11.

Authors

Xueqian Zhuang¹, Hao Zhang¹, Xiaoyan Li², Xiaoxun Li¹, Min Cong¹, Fangli Peng¹, Jingyi Yu¹, Xue Zhang¹, Qifeng Yang², Guohong Hu¹

Affiliations

¹ The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
² Department of Breast Surgery, Qilu Hospital of Shandong University, Ji'nan 250012, China.

PMID: 28892080
DOI: 10.1038/ncb3613

Abstract

Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and neutrophil recruitment in lung metastases by antagonizing cancer cell non-canonical WNT/PCP-RAC1-JNK signalling. In the lungs, DKK1 also inhibits WNT/Ca²⁺-CaMKII-NF-κB signalling and suppresses LTBP1-mediated TGF-β secretion of cancer cells. In contrast, DKK1 promotes breast-to-bone metastasis by regulating canonical WNT signalling of osteoblasts. Importantly, targeting canonical WNT may not be beneficial to treatment of metastatic cancer, while combinatory therapy against JNK and TGF-β signalling effectively prevents metastasis to both the lungs and bone. Thus, DKK1 represents a class of Janus-faced molecules with dichotomous roles in organotropic metastasis, and our data provide a rationale for new anti-metastasis approaches.

Publication types

Comparative Study

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Bone Neoplasms / genetics
Bone Neoplasms / metabolism*
Bone Neoplasms / prevention & control
Bone Neoplasms / secondary
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Calcium Signaling
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Cell Movement* / drug effects
Cyclooxygenase 2 / metabolism
Female
HeLa Cells
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism*
JNK Mitogen-Activated Protein Kinases / metabolism
Latent TGF-beta Binding Proteins / metabolism
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / prevention & control
Lung Neoplasms / secondary
Macrophages / metabolism
Macrophages / pathology
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy
NF-kappa B / metabolism
Neuropeptides / genetics
Neuropeptides / metabolism
Neutrophil Infiltration
Neutrophils / metabolism
Neutrophils / pathology
Osteoblasts / metabolism
Osteoblasts / pathology
RNA Interference
Time Factors
Transfection
Transforming Growth Factor beta1 / metabolism
Wnt Signaling Pathway* / drug effects
rac1 GTP-Binding Protein / genetics
rac1 GTP-Binding Protein / metabolism

Substances

Antineoplastic Agents
DKK1 protein, human
Dkk1 protein, mouse
Intercellular Signaling Peptides and Proteins
LTBP1 protein, human
Latent TGF-beta Binding Proteins
Ltbp1 protein, mouse
NF-kappa B
Neuropeptides
RAC1 protein, human
Rac1 protein, mouse
TGFB1 protein, human
Tgfb1 protein, mouse
Transforming Growth Factor beta1
Ptgs2 protein, mouse
Cyclooxygenase 2
PTGS2 protein, human
Calcium-Calmodulin-Dependent Protein Kinase Type 2
JNK Mitogen-Activated Protein Kinases
rac1 GTP-Binding Protein