Melanoma-derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment
Melanoma-derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment
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DOI：
10.1002/ijc.32521
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发表时间：
2019-11-01
影响因子：
6.4
通讯作者：
Erez, Neta
中科院分区：
文献类型：
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作者：
Lahav, Tzlil Gener;Adler, Omer;Erez, Neta
黑色素瘤死亡的主要原因是转移到远处器官，包括肺和脑。在肿瘤发生和转移的所有阶段，转移肿瘤细胞与继发部位的基质细胞的相互作用起着关键作用。转移微环境的变化被证明先于临床相关的转移，并且可能发生在播散的肿瘤细胞到达远处器官之前，从而产生了一个适宜的“转移前小生境”。“肿瘤细胞分泌的外泌体被证明在准备一个好客的转移性小生境中发挥重要作用。然而，黑色素瘤来源的外泌体对转移性龛形成的功能作用以及转移性龛处基质细胞中激活的下游途径在很大程度上尚未解决。在这里，我们表明，细胞外囊泡（EV）分泌的转移性黑色素瘤细胞，自发转移到肺和脑，激活肺成纤维细胞和星形胶质细胞中的促炎信号。有趣的是，与黑色素瘤细胞的旁分泌信号传导不同，转移性黑色素瘤细胞分泌的EV在肺成纤维细胞中引发促炎基因签名，但不激活伤口愈合功能，这表明肿瘤细胞分泌的EV激活不同的CAF特征和肿瘤促进功能。此外，黑色素瘤分泌的EV也激活了星形胶质细胞中的促炎信号传导，表明EV介导的基质细胞重编程是调节多个远端器官中转移性小生境的一般机制。因此，我们的研究表明，黑色素瘤衍生的EV以独特的方式重新编程基质细胞中的肿瘤促进功能，暗示肿瘤衍生的EV信号传导在促进炎性转移小生境形成中的核心作用。
The major cause of melanoma mortality is metastasis to distant organs, including lungs and brain. Reciprocal interactions of metastasizing tumor cells with stromal cells in secondary sites play a critical role in all stages of tumorigenesis and metastasis. Changes in the metastatic microenvironment were shown to precede clinically relevant metastases, and may occur prior to the arrival of disseminated tumor cells to the distant organ, thus creating a hospitable "premetastatic niche." Exosomes secreted by tumor cells were demonstrated to play an important role in the preparation of a hospitable metastatic niche. However, the functional role of melanoma-derived exosomes on metastatic niche formation, and the downstream pathways activated in stromal cells at the metastatic niche are largely unresolved. Here we show that extracellular vesicles (EVs) secreted by metastatic melanoma cells that spontaneously metastasize to lungs and to brain, activate proinflammatory signaling in lung fibroblasts and in astrocytes. Interestingly, unlike paracrine signaling by melanoma cells, EVs secreted by metastatic melanoma cells instigated a proinflammatory gene signature in lung fibroblasts but did not activate wound-healing functions, suggesting that tumor cell-secreted EVs activate distinct CAF characteristics and tumor-promoting functions. Moreover, melanoma-secreted EVs also activated proinflammatory signaling in astrocytes, indicating that EV-mediated reprogramming of stromal cells is a general mechanism of modulating the metastatic niche in multiple distant organs. Thus, our study demonstrates that melanoma-derived EVs reprogram tumor-promoting functions in stromal cells in a distinct manner, implicating a central role for tumor-derived EV signaling in promoting the formation of an inflammatory metastatic niche.