Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state
Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state
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DOI：
10.1038/ncb3021
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发表时间：
2014-09-01
影响因子：
21.3
通讯作者：
Khokha, Rama
中科院分区：
文献类型：
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作者：
Shimoda, Masayuki;Principe, Simona;Khokha, Rama
癌症相关成纤维细胞（CAF）驱动肿瘤进展，但这种细胞状态的出现知之甚少。由Timp基因家族控制的广谱金属蛋白酶影响人类癌症中的肿瘤微环境。在这里，我们产生四重TIMP敲除（无TIMP）成纤维细胞释放肿瘤间质隔室内的金属蛋白酶活性，并显示完全Timp损失足以获得标志性CAF功能。由无TIMP的成纤维细胞产生的外来体诱导癌细胞运动性和癌症干细胞标志物。这些外泌体的蛋白质组富含细胞外基质蛋白和金属蛋白酶ADAM 10。外泌体ADAM10通过Notch受体激活增加乳腺癌细胞中的醛脱氢酶表达，并通过GTdR RhoA增强运动性。此外，在无TIMP的成纤维细胞中敲低ADAM 10废除了它们的CAF功能。重要的是，人CAF分泌富含ADAM10的外泌体，其促进细胞运动并激活癌细胞中的RhoA和Notch信号传导。因此，跛行抑制了癌间质，其中活化的成纤维细胞分泌的外泌体影响肿瘤进展。
Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase activity within the tumour-stromal compartment and show that complete Timp loss is sufficient for the acquisition of hallmark CAF functions. Exosomes produced by TIMPless fibroblasts induce cancer cell motility and cancer stem cell markers. The proteome of these exosomes is enriched in extracellular matrix proteins and the metalloproteinase ADAM10. Exosomal ADAM10 increases aldehyde dehydrogenase expression in breast cancer cells through Notch receptor activation and enhances motility through the GTPase RhoA. Moreover, ADAM 10 knockdown in TIMPless fibroblasts abrogates their CAF function. Importantly, human CAFs secrete ADAM 10-rich exosomes that promote cell motility and activate RhoA and Notch signalling in cancer cells. Thus, limps suppress cancer stroma where activated-fibroblast-secreted exosomes impact tumour progression.