R01CA256911

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 an MCU-NRF2 signaling circuit. Through unbiased 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 Aim 1, we will use genetically engineered mouse models to investigate the role of 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.

Pennsylvania State University

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Hershey, Pennsylvania 170332360 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 384% from $655,433 to $3,172,802.