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

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 Biol

journal_title

Nature cell biology

authors

Zhuang X,Zhang H,Li X,Li X,Cong M,Peng F,Yu J,Zhang X,Yang Q,Hu G

doi

10.1038/ncb3613

subject

Has Abstract

pub_date

2017-10-01 00:00:00

pages

1274-1285

issue

10

eissn

1465-7392

issn

1476-4679

pii

ncb3613

journal_volume

19

pub_type

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