Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer.
Mitochondrial Calcium Uniporter Drives Metastasis and Confers a Targetable Cystine Dependency in Pancreatic Cancer.
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DOI：
10.1158/0008-5472.can-21-3230
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发表时间：
2022-06-15
期刊：
影响因子：
11.2
通讯作者：
Yang, Shengyu
中科院分区：
文献类型：
--
作者：
Wang, Xiuchao;Li, Yunzhan;Li, Zekun;Lin, Shengchen;Wang, Hongwei;Sun, Jianwei;Lan, Chungen;Wu, Liangliang;Sun, Dongxiao;Huang, Chongbiao;Singh, Pankaj K.;Hempel, Nadine;Trebak, Mohamed;DeNicola, Gina M.;Hao, Jihui;Yang, Shengyu
胰腺导管腺癌(PDAC)是一种高度转移性疾病，治疗效果不佳。在这里，我们发现线粒体钙单转运体(MCU)通过激活Keap1-Nrf2抗氧化程序促进PDAC细胞的迁移、侵袭、转移和代谢应激抵抗。半胱氨酸转运体SLC7A11被确定为MCU-Nrf2轴下游的一个可药物靶点。矛盾的是，尽管摄取半胱氨酸的能力增强，但MCU过表达的PDAC表现出典型的半胱氨酸剥夺细胞的特征，并且对半胱氨酸剥夺诱导的铁下垂敏感。SLC7A11的药理抑制剂有效地诱导了PDAC肿瘤的消退，并抑制了MCU诱导的转移。在患者来源的体外器官模型和体内患者来源的异种移植模型中，与MCU-Low肿瘤相比，MCU-High PDAC对SLC7A11抑制的敏感性增加。这些数据表明，MCU能够促进对代谢应激的抵抗，并以半胱氨酸依赖的方式驱动PDAC转移。MCU介导的半胱氨酸成瘾可以作为一种治疗漏洞来抑制PDAC肿瘤的生长和防止转移。
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacological inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared to MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and prevent metastasis.