Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity
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 adenocarcinoma (PDAC) is poorly understood. Here, we show that increased MCU expression is associated with malignancy and poorer outcomes in PDAC patients. 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 expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFß. Snail re-expression and TGFß 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. Overall design: Cell Lines developed from (KrasLSL-G12D/+; Trp53 LSL-R172H/+; Pdx1-Cre; R26LSL-Yfp/LSL-Yfp, 'KPCY' mice) with or without MCU floxed were used to develop stable, isogenic cell lines which express or do not express the gene for the mitochondrial calcium uniporter, Mcu. RNA was isolated with a RNeasy Mini kit (Qiagen 74104) from 10-15-cm dishes and sequenced by Novogene with a NovoSeq PE150 at ~20 M paired-end reads. Raw reads were processed with Salmon and DESeq2 before analysis.