Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity

Abstract

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 (Mcu^KO) 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 Mcu^KO cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.

Keywords: CP: Cancer; CP: Metabolism; EMT; MCU; PDAC; calcium signaling; cancer; epithelial-to-mesenchymal transition; metabolism; mitochondria; pancreas; uniporter.