Lung fibroblasts promote metastatic colonization through upregulation of stearoyl-CoA desaturase 1 in tumor cells
Lung fibroblasts promote metastatic colonization through upregulation of stearoyl-CoA desaturase 1 in tumor cells
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肺成纤维细胞通过上调肿瘤细胞中硬脂酰辅酶A去饱和酶1促进转移定植
DOI：
10.1038/s41388-017-0062-6
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发表时间：
2018-03-01
期刊：
影响因子：
8
通讯作者：
Luo, Yongzhang
中科院分区：
文献类型：
--
作者：
Liu, Guanghua;Feng, Shi;Luo, Yongzhang
作为转移的限速步骤，转移定植需要来自支持性基质的存活信号。然而，驱动这一过程的机制并不完全清楚。在这里，我们发现，B16 F10细胞的增殖被促进时，与肺成纤维细胞共培养。同时，B16 F10肿瘤细胞与小鼠肺成纤维细胞共注射显著增加肺转移。基于GEO数据库，我们确定硬脂酰辅酶A去饱和酶1（SCD 1）作为一种新的促进转移定植的因子。重要的是，我们发现成纤维细胞分泌的组织蛋白酶B（CTSB）通过膜联蛋白A2（ANXA 2）和PI 3 K/Akt/mTOR通路诱导B16 F10中SCD 1的上调。在B16 F10细胞中，升高的SCD 1诱导较高的单不饱和脂肪酸与饱和脂肪酸的比率。脂肪酸组成的变化有助于肿瘤细胞增殖和转移定植。此外，靶向SCD 1有效地抑制了肺转移，延长了小鼠的总体生存期。同时，SCD 1的表达与五种类型的癌症患者的无病生存率呈负相关。总的来说，我们的研究将SCD 1鉴定为肿瘤细胞增殖的关键调节剂，其由转移性小生境中的肺成纤维细胞分泌的组织蛋白酶B激活。我们的新发现为预防肿瘤转移提供了潜在的治疗靶点。
As a rate-limiting step in metastasis, metastatic colonization requires survival signals from supportive stroma. However, the mechanisms driving this process are incompletely understood. Here, we showed that the proliferation of B16F10 cells was promoted when cocultured with lung fibroblasts. Meanwhile, co-injection of B16F10 tumor cells with mouse lung fibroblasts significantly increased lung metastasis. Based on GEO database, we identified stearoyl-CoA desaturase 1 (SCD1) as a novel factor promoting metastatic colonization. Importantly, we found that fibroblast-secreted cathepsin B (CTSB) induced the upregulation of SCD1 in B16F10 through Annexin A2 (ANXA2) and PI3K/Akt/mTOR pathway. The elevated SCD1 induced a higher ratio of monounsaturated fatty acids to saturated fatty acids in B16F10 cells. The changes in fatty acid composition contributed to tumor cell proliferation and metastatic colonization. Furthermore, targeting SCD1 effectively inhibited lung metastasis and prolonged the overall survival of mice. Meanwhile, the expression of SCD1 was negatively correlated with disease-free survival in five types of cancer patients. Collectively, our study identifies SCD1 as a critical modulator of tumor cell proliferation that is activated by cathepsin B, secreted by lung fibroblasts at the metastatic niche. Our novel findings provide potential therapeutic targets to prevent tumor metastasis.