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.

中文翻译：

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Wnt信号抑制剂DKK1对乳腺癌的肺和骨转移的差异作用

转移性癌症是一种系统性疾病，转移决定因素可能会在各种靶器官中引起完全不同的作用。在这里，我们显示肿瘤分泌的DKK1是乳腺癌转移器官趋向性的血清学标志，并抑制肺转移。DKK1通过拮抗癌细胞的非常规WNT / PCP–RAC1–JNK信号传导，从而抑制PTGS2诱导的肺转移灶巨噬细胞和嗜中性白细胞募集。在肺部，DKK1还抑制WNT / Ca ²⁺-CaMKII-NF-κB信号传导并抑制LTBP1介导的癌细胞TGF-β分泌。相反，DKK1通过调节成骨细胞的经典WNT信号传导来促进乳房到骨的转移。重要的是，针对规范的WNT可能不利于转移癌的治疗，而针对JNK和TGF-β信号传导的联合治疗有效地防止了肺和骨的转移。因此，DKK1代表一类在促器官转移中具有两分作用的Janus面对分子，我们的数据为新的抗转移方法提供了理论依据。