Weissenrieder Jillian S, Peura Jessica, Paudel Usha, Bhalerao Nikita, Weinmann Natalie, Johnson Calvin, Wengyn Maximilian, Drager Rebecca, Furth Emma Elizabeth, Simin Karl, Ruscetti Marcus, Stanger Ben Z, Rustgi Anil K, Pitarresi Jason R, Foskett J Kevin
Department of Physiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
bioRxiv. 2024 Aug 9:2024.08.08.607195. doi: 10.1101/2024.08.08.607195.
Endoplasmic reticulum to mitochondria Ca transfer is important for cancer cell survival, but the role of mitochondrial Ca uptake through the mitochondrial Ca 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, deletion ( ) ablated mitochondrial Ca uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. 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 Ca uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGFβ. Snail re-expression and TGFβ treatment rescued deficits in cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.
内质网到线粒体的钙转运对癌细胞存活很重要，但线粒体通过线粒体钙单向转运体（MCU）摄取钙在胰腺腺癌（PDAC）中的作用却知之甚少。在此，我们表明MCU表达增加与PDAC患者的恶性程度及较差预后相关。在同基因小鼠PDAC模型中，基因敲除消除了线粒体钙摄取，这降低了细胞增殖并抑制了自我更新。原位植入无MCU的肿瘤细胞可减少原发性肿瘤生长和转移。基因敲除通过抑制上皮-间质转化（EMT）降低了肿瘤细胞的细胞可塑性，而EMT有助于PDAC的转移能力。从机制上讲，线粒体钙摄取的丧失降低了关键EMT转录因子Snail的表达以及EMT诱导配体TGFβ的分泌。Snail的重新表达和TGFβ处理挽救了基因敲除细胞中的缺陷并恢复了它们的转移能力。因此，MCU可能是PDAC中一个限制癌细胞诱导的EMT和转移的治疗靶点。
