Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity
Jillian S. Weissenrieder,
Jessica Peura,
Usha Paudel,
Nikita Bhalerao,
Natalie Weinmann,
Calvin Johnson,
Maximilian Wengyn,
Rebecca Drager,
Emma Elizabeth Furth,
Karl Simin,
Marcus Ruscetti,
Ben Z. Stanger,
Anil K. Rustgi,
Jason R. Pitarresi,
J. Kevin Foskett
Affiliations
Jillian S. Weissenrieder
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Jessica Peura
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Usha Paudel
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Nikita Bhalerao
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Natalie Weinmann
Department of Chemistry, Millersville University, Millersville, PA, USA
Calvin Johnson
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Maximilian Wengyn
Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-5157, USA
Rebecca Drager
Department of Chemistry, The Ohio State University, Columbus, OH, USA
Emma Elizabeth Furth
Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Karl Simin
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Marcus Ruscetti
Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
Ben Z. Stanger
Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-5157, USA
Anil K. Rustgi
Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Irving Medical Center, New York City, NY 10032, USA
Jason R. Pitarresi
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Corresponding author
J. Kevin Foskett
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA; Corresponding author
Summary: Endoplasmic reticulum to mitochondria Ca2+ transfer is important for cancer cell survival, but the role of mitochondrial Ca2+ uptake through the mitochondrial Ca2+ uniporter (MCU) in pancreatic ductal adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in patients with PDAC. In isogenic murine PDAC models, Mcu deletion (McuKO) ablated mitochondrial Ca2+ uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. Mcu deletion reduced the cellular plasticity of tumor cells by inhibiting epithelial-to-mesenchymal transition (EMT), which contributes to metastatic competency in PDAC. Mechanistically, the loss of mitochondrial Ca2+ uptake reduced the expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF-β. Snail re-expression and TGF-β treatment rescued deficits in McuKO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.
