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.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Zhuang X,Zhang H,Li X,Li X,Cong M,Peng F,Yu J,Zhang X,Yang Q,Hu Gdoi
10.1038/ncb3613subject
Has Abstractpub_date
2017-10-01 00:00:00pages
1274-1285issue
10eissn
1465-7392issn
1476-4679pii
ncb3613journal_volume
19pub_type
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