Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs.
Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs.
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癌细胞中化疗诱导的应激反应的系统水平分析揭示了可药物化的权衡。
DOI：
10.1073/pnas.2018229118
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发表时间：
2021-04-27
影响因子：
11.1
通讯作者：
Auner HW
中科院分区：
文献类型：
--
作者：
Saavedra-García P;Roman-Trufero M;Al-Sadah HA;Blighe K;López-Jiménez E;Christoforou M;Penfold L;Capece D;Xiong X;Miao Y;Parzych K;Caputo VS;Siskos AP;Encheva V;Liu Z;Thiel D;Kaiser MF;Piazza P;Chaidos A;Karadimitris A;Franzoso G;Snijders AP;Keun HC;Oyarzún DA;Barahona M;Auner HW
癌症治疗通常无法治愈患者，因为一部分肿瘤细胞承受化疗的毒性作用。存活的癌细胞如何从亚致死药物诱导的应激中恢复尚不清楚，但考虑到细胞资源是有限的，应激的解决可能以牺牲不太重要的系统为代价。在这里，我们研究了骨髓癌，多发性骨髓瘤，蛋白酶体抑制后，一种常用的治疗方法的压力积累和解决的全球细胞事件。使用时间的多组学方法，我们描绘了出乎意料的复杂和持久的变化骨髓瘤细胞在应力分辨率过程中进行，并证明恢复细胞比急性应激细胞更容易受到特定的侮辱。因此，这些发现可能为优化癌症治疗提供途径。癌细胞可以在化疗诱导的压力下生存，但它们如何从中恢复尚不清楚。使用时间多组学方法，我们描绘了全球机制的蛋白毒性应激决议在多发性骨髓瘤细胞恢复蛋白酶体抑制。我们的观察定义了分层和长期的程序，包括广泛的变化，在转录组，蛋白质组和代谢组的压力解决。细胞从蛋白酶体抑制中恢复涉及葡萄糖和脂质代谢的长期和动态变化以及线粒体功能的抑制。我们证明，恢复细胞比急性应激细胞更容易受到特定的侮辱，并确定一般控制非去阻遏蛋白2（GCN 2）驱动的细胞对氨基酸缺乏的反应作为一个关键的恢复相关的脆弱性。使用转录组分析管道，我们进一步表明GCN 2也是共享分子特征的实体癌的转录特征定义子集中的压力无关的真正目标。因此，识别与肿瘤细胞中化疗诱导的应激的解决相关的细胞权衡可以揭示癌症治疗优化的新的治疗靶点和途径。
Cancer therapies often fail to cure patients because a proportion of tumor cells withstand the toxic effects of chemotherapy. How surviving cancer cells recover from sublethal drug-induced stress is not known, but given that cellular resources are finite, stress resolution may come at the expense of less essential systems. Here, we studied the global cellular events of stress buildup and resolution in the bone marrow cancer, multiple myeloma, after proteasome inhibition, a commonly used therapeutic approach. Using a temporal multiomics approach, we delineate the unexpectedly complex and protracted changes myeloma cells undergo during stress resolution and demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells. Thus, the findings may provide avenues for optimizing cancer therapies. Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known. Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stress resolution in multiple myeloma cells recovering from proteasome inhibition. Our observations define layered and protracted programs for stress resolution that encompass extensive changes across the transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibition involved protracted and dynamic changes of glucose and lipid metabolism and suppression of mitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellular response to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptome analysis pipeline, we further show that GCN2 is also a stress-independent bona fide target in transcriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus, identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumor cells may reveal new therapeutic targets and routes for cancer therapy optimization.
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影响因子：
13.6
作者：
Benjamin D;Colombi M;Hindupur SK;Betz C;Lane HA;El-Shemerly MY;Lu M;Quagliata L;Terracciano L;Moes S;Sharpe T;Wodnar-Filipowicz A;Moroni C;Hall MN
通讯作者：
Hall MN
影响因子：
7.7
作者：
Acosta-Alvear D;Cho MY;Wild T;Buchholz TJ;Lerner AG;Simakova O;Hahn J;Korde N;Landgren O;Maric I;Choudhary C;Walter P;Weissman JS;Kampmann M
通讯作者：
Kampmann M
影响因子：
8.8
作者：
Benjamin, Don;Robay, Dimitri;Hall, Michael N.
通讯作者：
Hall, Michael N.
影响因子：
9.9
作者：
Kamrad, Stephan;Grossbach, Jan;Bahler, Jurg
通讯作者：
Bahler, Jurg
影响因子：
50.3
作者：
Elgendy, Mohamed;Ciro, Marco;Minucci, Saverio
通讯作者：
Minucci, Saverio