Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness.
Tumour cell-derived Wnt7a recruits and activates fibroblasts to promote tumour aggressiveness.
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DOI：
10.1038/ncomms10305
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发表时间：
2016-01-18
影响因子：
16.6
通讯作者：
Isacke CM
中科院分区：
文献类型：
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作者：
Avgustinova A;Iravani M;Robertson D;Fearns A;Gao Q;Klingbeil P;Hanby AM;Speirs V;Sahai E;Calvo F;Isacke CM
基质成纤维细胞募集到肿瘤中并活化为癌症相关成纤维细胞（CAF）表型，这与促进原发性肿瘤生长和进展为转移性疾病有关。然而，肿瘤的潜在机制：驱动肿瘤间质异质性的成纤维细胞串扰仍然知之甚少。使用体内模型，我们确定Wnt7a是由侵袭性乳腺肿瘤细胞专门分泌的关键因子，其诱导CAF转化。在功能上，这导致细胞外基质重塑，为肿瘤细胞侵袭和促进远处转移创造一个允许的环境。从机制上讲，Wnt7a介导的成纤维细胞活化不依赖于经典的Wnt信号传导。相反，我们证明了Wnt7a在体外和体内3D模型中增强TGFβ受体信号传导，从而突出了发育和疾病中两个关键信号传导途径之间的相互作用。重要的是，在临床乳腺癌队列中，肿瘤细胞Wnt7a表达与促纤维增生、预后不良的基质和患者预后不良相关。 癌症相关的成纤维细胞如何被激活以支持转移尚不清楚。在这里，Avgustinova等人表明，肿瘤细胞来源的Wnt7a激活成纤维细胞中的TGFβ信号传导，诱导它们将微环境重塑到促进肿瘤侵袭和转移的状态。
Stromal fibroblast recruitment to tumours and activation to a cancer-associated fibroblast (CAF) phenotype has been implicated in promoting primary tumour growth and progression to metastatic disease. However, the mechanisms underlying the tumour:fibroblast crosstalk that drive the intertumoural stromal heterogeneity remain poorly understood. Using in vivo models we identify Wnt7a as a key factor secreted exclusively by aggressive breast tumour cells, which induces CAF conversion. Functionally, this results in extracellular matrix remodelling to create a permissive environment for tumour cell invasion and promotion of distant metastasis. Mechanistically, Wnt7a-mediated fibroblast activation is not dependent on classical Wnt signalling. Instead, we demonstrate that Wnt7a potentiates TGFβ receptor signalling both in 3D in vitro and in vivo models, thus highlighting the interaction between two of the key signalling pathways in development and disease. Importantly, in clinical breast cancer cohorts, tumour cell Wnt7a expression correlates with a desmoplastic, poor-prognosis stroma and poor patient outcome. How cancer-associated fibroblasts become activated to support metastasis is not well understood. Here, Avgustinova et al. show that tumour cell-derived Wnt7a activates TGFβ signaling in fibroblasts, inducing them to remodel the microenvironment to the state, which promotes tumour invasiveness and metastasis.