胱氨酸
癌症研究
转移
胰腺癌
癌细胞
细胞迁移
癌症
生物
化学
细胞
医学
生物化学
内科学
半胱氨酸
酶
作者
Xiuchao Wang,Yunzhan Li,Zekun Li,Shengchen Lin,Hongwei Wang,Jianwei Sun,Chungen Lan,Liangliang Wu,Dongxiao Sun,Chongbiao Huang,Pankaj K. Singh,Nadine Hempel,Mohamed Trebak,Gina M. DeNicola,Jihui Hao,Shengyu Yang
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2022-04-12
卷期号:82 (12): 2254-2268
被引量:30
标识
DOI:10.1158/0008-5472.can-21-3230
摘要
Abstract 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. Pharmacologic 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 with MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and to 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 to prevent metastasis. Significance: Elevated mitochondrial calcium uptake in PDAC promotes metastasis but exposes cystine addiction and ferroptosis sensitivity that could be targeted to improve pancreatic cancer treatment.
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