Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis.
Copper depletion modulates mitochondrial oxidative phosphorylation to impair triple negative breast cancer metastasis.
复制标题
铜缺乏调节线粒体氧化磷酸化，损害三阴性乳腺癌转移。
DOI：
10.1038/s41467-021-27559-z
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发表时间：
2021-12-15
影响因子：
16.6
通讯作者：
Mittal V
中科院分区：
文献类型：
--
作者：
Ramchandani D;Berisa M;Tavarez DA;Li Z;Miele M;Bai Y;Lee SB;Ban Y;Dephoure N;Hendrickson RC;Cloonan SM;Gao D;Cross JR;Vahdat LT;Mittal V
铜作为一种辅助因子的主机金属酶，有助于恶性进展。口服生物可利用的铜螯合剂四硫代钼酸盐（TM）与高风险三阴性乳腺癌（TNBC）患者的显著生存益处相关。尽管有这些有希望的数据，铜消耗影响转移的机制知之甚少，这仍然是推进TM随机II期试验的主要障碍。在这里，使用两个独立的TNBC模型，我们报告了原发性肿瘤中高度转移的SOX 2/OCT 4+细胞的离散亚群，其表现出细胞内铜水平升高和对TM的显著敏感性。全球蛋白质组学和代谢组学分析将TM介导的复合物IV失活鉴定为SOX 2/OCT 4+细胞群体中的主要代谢缺陷。我们还确定了AMPK/mTORC 1能量传感器作为一个重要的下游途径，并表明AMPK抑制拯救TM介导的入侵损失。此外，损失的特定铜伴侣，COX 17，限制铜缺乏线粒体和phenocopies TM介导的改变。这些发现确定了一个铜代谢转移轴，有可能在下一代治疗试验中丰富患者人群。据报道，铜缺乏可改善三阴性乳腺癌（TNBC）患者的生存率，但其潜在机制尚未完全了解。在这里，作者表明，铜螯合减少线粒体氧化磷酸化，导致TNBC转移减少。
Copper serves as a co-factor for a host of metalloenzymes that contribute to malignant progression. The orally bioavailable copper chelating agent tetrathiomolybdate (TM) has been associated with a significant survival benefit in high-risk triple negative breast cancer (TNBC) patients. Despite these promising data, the mechanisms by which copper depletion impacts metastasis are poorly understood and this remains a major barrier to advancing TM to a randomized phase II trial. Here, using two independent TNBC models, we report a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit elevated intracellular copper levels and a marked sensitivity to TM. Global proteomic and metabolomic profiling identifies TM-mediated inactivation of Complex IV as the primary metabolic defect in the SOX2/OCT4+ cell population. We also identify AMPK/mTORC1 energy sensor as an important downstream pathway and show that AMPK inhibition rescues TM-mediated loss of invasion. Furthermore, loss of the mitochondria-specific copper chaperone, COX17, restricts copper deficiency to mitochondria and phenocopies TM-mediated alterations. These findings identify a copper-metabolism-metastasis axis with potential to enrich patient populations in next-generation therapeutic trials. Copper depletion has been reported to improve survival in patients with triple negative breast cancer (TNBC) but the underlying mechanisms are not completely understood. Here, the authors show that copper chelation reduces mitochondrial oxidative phosphorylation leading to decreased TNBC metastasis.
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影响因子：
3.9
作者：
Gowans GJ;Hardie DG
通讯作者：
Hardie DG
DOI：
10.1073/pnas.1910722117
发表时间：
2020-01-28
影响因子：
11.1
作者：
Blockhuys, Stephanie;Zhang, Xiaolu;Wittung-Stafshede, Pernilla
通讯作者：
Wittung-Stafshede, Pernilla
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
DOI：
10.1073/pnas.86.21.8427
发表时间：
1989-11-01
影响因子：
11.1
作者：
BADET, J;SONCIN, F;BARRITAULT, D
通讯作者：
BARRITAULT, D
影响因子：
3.7
作者：
Berven, LA;Willard, FS;Crouch, MF
通讯作者：
Crouch, MF