Mitochondrial calcium signaling in pancreatic cancer metastasis and progression

The goals of this research plan are to uncover the molecular mechanism by which mitochondrial Ca2+ signaling promotes pancreatic ductal adenocarcinoma (PDAC) cell migration, invasion and metastasis, and to devise novel strategies to exploit potential therapeutic vulnerability in metastatic PDAC based on our mechanistic studies. The Mitochondrial Calcium Uniporter (MCU) is the only Ca2+ channel on the mitochondrial inner membrane responsible for mitochondrial Ca2+ uptake. Under certain pathological conditions, MCU-mediated mitochondrial Ca2+ overload leads to cell death. Paradoxically, MCU levels are significantly increased during the progression of several types of cancer. In this proposal we use PDAC as a model to study the molecular mechanism by which MCU controls cancer metastasis and progression. Our data indicated that MCU overexpression in PDAC promotes PDAC cell migration, invasion and metastasis through a MCU-Nrf2 signaling circuit. Through non- biased RNA sequencing and interrogation of the TCGA transcriptomic datasets, we identified xCT (SLC7A11, the functional subunit of the cystine / glutamate antiporter system) as a potentially druggable target in MCU- mediated anti-oxidant response and PDAC metastasis. Intriguingly MCU overexpressing PDAC cells are addicted to xCT-mediated cystine uptake. When PDAC cells were deprived of cystine or treated with xCT inhibitors, MCU promotes ferroptosis, a form of lipid ROS-mediated, iron-dependent regulated cell death. In Aim1 we will use genetically engineered mouse model to investigate the role MCU-Nrf2 signaling in PDAC metastasis and progression. We will determine the mechanism by which MCU activates Nrf2 in Aim 2 and define cystine addiction as a therapeutic vulnerability in MCU overexpressing PDAC in Aim 3. The success of this proposal will provide important mechanistic insight for mitochondrial calcium signaling in PDAC metastasis, and will likely provide a novel avenue to prevent metastatic recurrence in PDAC.