Researchers at Tianjin Medical University Cancer Institute and Hospital in Tianjin, China, in collaboration with U.S. researchers, found that the mechanism, called mitochondrial calcium uniporter (MCU), drives metastasis and confers a targetable cystine dependency in pancreatic cancer.

More than 75% of pancreatic ductal adenocarcinoma (PDAC) patients will develop liver metastasis within 1-2 years after complete removal of the primary tumor, and the 5-year survival rate is less than 10%. Mitochondrial calcium regulation by MCU plays a crucial role in pancreatic cancer tumorigenesis and progression.

In their paper, the researchers showed how MCU correlates with poor progression and metastasis in pancreatic cancer patients and drives metabolic stress resistance by activating the Keap1-Nrf2 antioxidant pathway in pancreatic cancer preclinical models. MCU-mediated transcriptomic changes revealed that cystine transporter solute carrier family 7 member 11 (SLC7A11) is downstream of the MCU-Nrf2 axis and could be targeted.

Pharmacological inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis for in vivo PDAC models. In addition, the researchers demonstrated that elevated mitochondrial calcium uptake in PDAC promotes metastasis but exposes cystine addiction and ferroptosis sensitivity that could be targeted by inhibition of SL7A11.

Overall, this study reveals a novel finding that MCU can promote resistance to metabolic stress and drive metastasis in a cystine-dependent manner in pancreatic cancer. Therefore, MCU-mediated cystine addiction could be exploited as a therapeutic option in pancreatic cancer.