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-kappa B signalling and suppresses LTBP1-mediated TGF-beta 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-beta 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.
[1]Chinese Acad Sci & Shanghai Jiao Tong Univ, Sch Med, Univ Chinese Acad Sci,The Key Lab Stem Cell Biology, Inst Hlth Sci, Shanghai Inst Biological Sci, Shanghai 200031, China.
[2]Shandong Univ, Qilu Hosp, Dept Breast Surg, Jinan 250012, China.
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