Exosomes mediate intercellular transfer of non-autonomous tolerance to proteasome inhibitors in mixed-lineage leukemia
Exosomes mediate intercellular transfer of non-autonomous tolerance to proteasome inhibitors in mixed-lineage leukemia
复制标题
外泌体介导混合谱系白血病中蛋白酶体抑制剂非自主耐受的细胞间转移。
DOI：
10.1111/cas.14351
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发表时间：
2020-04-01
期刊：
影响因子：
5.7
通讯作者：
Liu, Han
中科院分区：
文献类型：
--
作者：
Ge, Maolin;Qiao, Zhi;Liu, Han
蛋白酶体抑制剂显著改善癌症预后，但它们的使用最终会导致蛋白酶体抑制剂耐药和复发。目前对蛋白酶体抑制剂耐药性的了解仅限于细胞自主机制，非自主机制是否与蛋白酶体抑制剂耐药性的发生发展有关尚不清楚。在这里，我们表明，蛋白酶体抑制耐受性可以通过外切体介导的细胞间相互作用而非自主地传递。我们发现，在混合系白血病细胞中，可逆的蛋白酶体抑制物耐药可以通过外切体介导的细胞周期停滞和干细胞增强而从治疗应激下的细胞传递到原始敏感细胞。综合多组学分析，通过相互作用事件扩散算法确定了几个候选外体蛋白，它们可能是蛋白酶体抑制剂耐药性的预测因子，也是治疗难治性混合系白血病的潜在治疗靶点。此外，抑制外切体的分泌是在体内逆转蛋白酶体抑制剂耐药性的一种有前景的策略，这为其他难治性或复发性癌症的治疗提供了新的原理证据。
Proteasome inhibitors significantly improve cancer outcomes, but their use is eventually followed by proteasome inhibitor resistance and relapse. Current understanding of proteasome inhibitor resistance is limited to cell-autonomous mechanisms; whether non-autonomous mechanisms can be implicated in the development of proteasome inhibitor resistance is unclear. Here, we show that proteasome inhibitor tolerance can be transmitted non-autonomously through exosome-mediated intercellular interactions. We revealed that reversible proteasome inhibitor resistance can be transmitted from cells under therapy stress to naive sensitive cells through exosome-mediated cell cycle arrest and enhanced stemness in mixed-lineage leukemia cells. Integrated multi-omics analysis using the Tied Diffusion through Interacting Events algorithm identified several candidate exosomal proteins that may serve as predictors for proteasome inhibitor resistance and potential therapeutic targets for treating refractory mixed-lineage leukemia. Furthermore, inhibiting the secretion of exosomes is a promising strategy for reversing proteasome inhibitor resistance in vivo, which provides a novel proof of principle for the treatment of other refractory or relapsed cancers.