{"doi":"10.1016/j.celrep.2025.115627","title":"Mitochondrial Ca2+ controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity","abstract":"<h2>Summary</h2> Endoplasmic reticulum to mitochondria Ca<sup>2+</sup> transfer is important for cancer cell survival, but the role of mitochondrial Ca<sup>2+</sup> uptake through the mitochondrial Ca<sup>2+</sup> 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, <i>Mcu</i> deletion (<i>Mcu</i><sup>KO</sup>) ablated mitochondrial Ca<sup>2+</sup> uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis. <i>Mcu</i> 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<sup>2+</sup> 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 <i>Mcu</i><sup>KO</sup> cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.","journal":"Cell Reports","year":2025,"id":517336,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9541,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1032165,"name":"Jessica Peura","orcid":"0000-0002-7226-2232","position":1,"is_corresponding":false},{"id":1042120,"name":"Usha Paudel","orcid":null,"position":2,"is_corresponding":false},{"id":303928,"name":"Nikita Bhalerao","orcid":"0009-0007-1633-4389","position":3,"is_corresponding":false},{"id":1337545,"name":"Natalie Weinmann","orcid":null,"position":4,"is_corresponding":false},{"id":1337168,"name":"Calvin W. Johnson","orcid":"0000-0003-1059-7384","position":5,"is_corresponding":false},{"id":637720,"name":"Maximilian D. Wengyn","orcid":null,"position":6,"is_corresponding":false},{"id":1337546,"name":"Rebecca Drager","orcid":null,"position":7,"is_corresponding":false},{"id":251376,"name":"Emma E. Furth","orcid":"0000-0002-9309-985X","position":8,"is_corresponding":false},{"id":599961,"name":"Karl Simin","orcid":"0000-0002-7431-0939","position":9,"is_corresponding":false},{"id":228772,"name":"Marcus Ruscetti","orcid":"0000-0002-4394-2087","position":10,"is_corresponding":false},{"id":106462,"name":"Ben Z. Stanger","orcid":"0000-0003-0410-4037","position":11,"is_corresponding":false},{"id":612091,"name":"Anil K. Rustgi","orcid":"0000-0002-5877-7993","position":12,"is_corresponding":false},{"id":296416,"name":"Jason R. Pitarresi","orcid":"0000-0001-9549-4768","position":13,"is_corresponding":false},{"id":260391,"name":"J. Kevin Foskett","orcid":"0000-0002-8854-0268","position":14,"is_corresponding":false},{"id":1041388,"name":"Jillian Weissenrieder","orcid":"0000-0002-8096-5421","position":0,"is_corresponding":true}],"reference_count":59,"raw_metadata":null,"created_at":"2026-07-19T02:48:59.410472Z","pmid":"40286270","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}