Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling.
Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling.
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耐药癌细胞来源的外泌体 EphA2 通过 EphA2-Ephrin A1 反向信号促进乳腺癌转移
DOI：
10.1038/s41419-021-03692-x
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发表时间：
2021-04-20
影响因子：
9
通讯作者：
Zhang F
中科院分区：
文献类型：
--
作者：
Gao Z;Han X;Zhu Y;Zhang H;Tian R;Wang Z;Cui Y;Wang Z;Niu R;Zhang F
耐药性引起的肿瘤转移是成功癌症治疗的主要挑战。然而，耐药性的促侵袭和转移能力的机制仍然难以捉摸。肿瘤微环境中癌细胞和基质细胞之间外泌体介导的细胞间通讯是癌症发生和进展所必需的。最近的报告表明，癌细胞之间的通讯也会促进肿瘤的侵袭。然而，这方面却很少受到重视。在此，我们证明耐药细胞来源的外泌体促进敏感乳腺癌细胞的侵袭。定量蛋白质组分析表明EphA2富含来自耐药细胞的外泌体。外泌体EphA2赋予从耐药细胞到敏感细胞的侵袭/转移表型转移。此外，外泌体EphA2通过配体Ephrin A1依赖性反向途径而不是正向途径激活ERK1/2信号传导，从而促进乳腺癌进展。我们的研究结果表明，外泌体 EphA2 在不依赖于直接细胞间接触的癌细胞之间侵袭性表型的传递中发挥着关键功能作用。我们的研究还表明，耐药细胞来源的外泌体中 EphA2 的增加可能是化疗/耐药诱导乳腺癌进展的重要机制。
Tumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
12.4
作者：
Fan, Jia;Wei, Qian;Hu, Ye
通讯作者：
Hu, Ye
DOI：
10.1073/pnas.72.9.3585
发表时间：
1975-01-01
影响因子：
11.1
作者：
MINTZ, B;ILLMENSEE, K
通讯作者：
ILLMENSEE, K
影响因子：
78.5
作者：
Chabner, BA;Roberts, TG
通讯作者：
Roberts, TG
影响因子：
7.3
作者：
Beauchamp, Amanda;Debinski, Waldemar
通讯作者：
Debinski, Waldemar