{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T21:58:04Z","timestamp":1770328684556,"version":"3.49.0"},"posted":{"date-parts":[[2024,8,9]]},"group-title":"Cancer Biology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T00:00:00Z","timestamp":1723161600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,8,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Endoplasmic reticulum to mitochondria Ca\n                  <jats:sup>2+<\/jats:sup>\n                  transfer is important for cancer cell survival, but the role of mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  uptake through the mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  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,\n                  <jats:italic>Mcu<\/jats:italic>\n                  deletion (\n                  <jats:italic>Mcu<\/jats:italic>\n                  <jats:sup>KO<\/jats:sup>\n                  ) ablated mitochondrial Ca\n                  <jats:sup>2+<\/jats:sup>\n                  uptake, which reduced proliferation and inhibited self-renewal. Orthotopic implantation of MCU-null tumor cells reduced primary tumor growth and metastasis.\n                  <jats:italic>Mcu<\/jats:italic>\n                  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\n                  <jats:sup>2+<\/jats:sup>\n                  uptake reduced expression of the key EMT transcription factor Snail and secretion of the EMT-inducing ligand TGF\u03b2. Snail re-expression and TGF\u03b2 treatment rescued deficits in\n                  <jats:italic>Mcu<\/jats:italic>\n                  <jats:sup>KO<\/jats:sup>\n                  cells and restored their metastatic ability. Thus, MCU may present a therapeutic target in PDAC to limit cancer-cell-induced EMT and metastasis.\n                <\/jats:p>","DOI":"10.1101\/2024.08.08.607195","type":"posted-content","created":{"date-parts":[[2024,8,9]],"date-time":"2024-08-09T16:30:19Z","timestamp":1723221019000},"source":"Crossref","is-referenced-by-count":1,"title":["Mitochondrial Ca\n                  <sup>2+<\/sup>\n                  controls pancreatic cancer growth and metastasis by regulating epithelial cell plasticity"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8096-5421","authenticated-orcid":false,"given":"Jillian S.","family":"Weissenrieder","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica","family":"Peura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Usha","family":"Paudel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikita","family":"Bhalerao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie","family":"Weinmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Calvin","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximilian","family":"Wengyn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Drager","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma Elizabeth","family":"Furth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karl","family":"Simin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4394-2087","authenticated-orcid":false,"given":"Marcus","family":"Ruscetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0410-4037","authenticated-orcid":false,"given":"Ben Z.","family":"Stanger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anil K.","family":"Rustgi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason R.","family":"Pitarresi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Kevin","family":"Foskett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024081300101178000_2024.08.08.607195v1.1","unstructured":"SEER. Surveillance, Epidemiology, and End Results (SEER) Program Populations. (2022)."},{"key":"2024081300101178000_2024.08.08.607195v1.2","doi-asserted-by":"publisher","DOI":"10.1126\/stke.2152004re1"},{"key":"2024081300101178000_2024.08.08.607195v1.3","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21820"},{"key":"2024081300101178000_2024.08.08.607195v1.4","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa032295"},{"key":"2024081300101178000_2024.08.08.607195v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.08.009"},{"key":"2024081300101178000_2024.08.08.607195v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00499"},{"key":"2024081300101178000_2024.08.08.607195v1.7","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39104"},{"key":"2024081300101178000_2024.08.08.607195v1.8","doi-asserted-by":"publisher","DOI":"10.1097\/CCO.0b013e32835b6371"},{"key":"2024081300101178000_2024.08.08.607195v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2013.01.008"},{"key":"2024081300101178000_2024.08.08.607195v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3758"},{"key":"2024081300101178000_2024.08.08.607195v1.11","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.095299"},{"key":"2024081300101178000_2024.08.08.607195v1.12","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202051872"},{"key":"2024081300101178000_2024.08.08.607195v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2018.05.027"},{"key":"2024081300101178000_2024.08.08.607195v1.14","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202051872"},{"key":"2024081300101178000_2024.08.08.607195v1.15","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-0779-4_24"},{"key":"2024081300101178000_2024.08.08.607195v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.11.025"},{"key":"2024081300101178000_2024.08.08.607195v1.17","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-385233-5.00002-7"},{"key":"2024081300101178000_2024.08.08.607195v1.18","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/8480762"},{"key":"2024081300101178000_2024.08.08.607195v1.19","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1407717111"},{"key":"2024081300101178000_2024.08.08.607195v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.12.001"},{"key":"2024081300101178000_2024.08.08.607195v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0040-3"},{"key":"2024081300101178000_2024.08.08.607195v1.22","doi-asserted-by":"publisher","DOI":"10.1159\/000512277"},{"key":"2024081300101178000_2024.08.08.607195v1.23","doi-asserted-by":"publisher","DOI":"10.1186\/s12576-023-00878-0"},{"key":"2024081300101178000_2024.08.08.607195v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.18"},{"key":"2024081300101178000_2024.08.08.607195v1.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.03.045"},{"key":"2024081300101178000_2024.08.08.607195v1.26","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1082213"},{"key":"2024081300101178000_2024.08.08.607195v1.27","doi-asserted-by":"publisher","DOI":"10.1186\/1478-811X-9-19"},{"key":"2024081300101178000_2024.08.08.607195v1.28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-21-3230"},{"key":"2024081300101178000_2024.08.08.607195v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-020-0155-5"},{"key":"2024081300101178000_2024.08.08.607195v1.30","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102628"},{"key":"2024081300101178000_2024.08.08.607195v1.31","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-018-2162-8"},{"key":"2024081300101178000_2024.08.08.607195v1.32","doi-asserted-by":"publisher","DOI":"10.2174\/1568009624666230912095526"},{"key":"2024081300101178000_2024.08.08.607195v1.33","doi-asserted-by":"publisher","DOI":"10.2174\/1566524022666220617143754"},{"key":"2024081300101178000_2024.08.08.607195v1.34","doi-asserted-by":"publisher","DOI":"10.3390\/cells11131993"},{"key":"2024081300101178000_2024.08.08.607195v1.35","doi-asserted-by":"publisher","DOI":"10.3390\/cells9061407"},{"key":"2024081300101178000_2024.08.08.607195v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.12.021"},{"key":"2024081300101178000_2024.08.08.607195v1.37","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.06.006"},{"key":"2024081300101178000_2024.08.08.607195v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.081"},{"key":"2024081300101178000_2024.08.08.607195v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2008.03.004"},{"key":"2024081300101178000_2024.08.08.607195v1.40","doi-asserted-by":"publisher","DOI":"10.1242\/dev.01907"},{"key":"2024081300101178000_2024.08.08.607195v1.41","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202254746"},{"key":"2024081300101178000_2024.08.08.607195v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.07.019"},{"key":"2024081300101178000_2024.08.08.607195v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jare.2024.02.013"},{"key":"2024081300101178000_2024.08.08.607195v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2868"},{"key":"2024081300101178000_2024.08.08.607195v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.07.009"},{"key":"2024081300101178000_2024.08.08.607195v1.46","doi-asserted-by":"publisher","DOI":"10.15430\/JCP.2020.25.4.213"},{"key":"2024081300101178000_2024.08.08.607195v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.104380"},{"key":"2024081300101178000_2024.08.08.607195v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17204-5"},{"key":"2024081300101178000_2024.08.08.607195v1.49","doi-asserted-by":"publisher","DOI":"10.1159\/000502562"},{"key":"2024081300101178000_2024.08.08.607195v1.50","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot078360"},{"key":"2024081300101178000_2024.08.08.607195v1.51","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-20-1098"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.08.08.607195","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T06:50:30Z","timestamp":1768459830000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2024.08.08.607195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,9]]},"references-count":51,"URL":"https:\/\/doi.org\/10.1101\/2024.08.08.607195","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1016\/j.celrep.2025.115627","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2024,8,9]]},"subtype":"preprint"}}