{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:44:48Z","timestamp":1789170288943,"version":"build-2803163510"},"reference-count":54,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:00:00Z","timestamp":1644537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Most patients with pancreatic cancer develop cachexia, which is characterized by progressive muscle loss. The mechanisms underlying muscle loss in cancer cachexia remain elusive. Pancreatic tumour organoids are 3D cell culture models that retain key characteristics of the parent tumour. We aimed to investigate the effect of pancreatic tumour organoid\u2010derived factors on processes that determine skeletal muscle mass, including the regulation of muscle protein turnover and myogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Conditioned medium (CM) was collected from human pancreatic cancer cell lines (PK\u201045H, PANC\u20101, PK\u20101, and KLM\u20101), pancreatic tumour organoid cultures from a severely cachectic (PANCO\u20109a) and a non\u2010cachectic patient (PANCO\u201012a), and a normal pancreas organoid culture. Differentiating C2C12 myoblasts and mature C2C12 myotubes were exposed to CM for 24\u00a0h or maintained in control medium. In myotubes, NF\u2010kB activation was monitored using a NF\u2010\u03baB luciferase reporter construct, and mRNA expression of E3\u2010ubiquitin ligases and <jats:italic>REDD1<\/jats:italic> was analysed by RT\u2010qPCR. C2C12 myoblast proliferation and differentiation were monitored by live cell imaging and myogenic markers and myosin heavy chain (MyHC) isoforms were assessed by RT\u2010qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Whereas CM from PK\u20101 and KLM\u20101 cells significantly induced NF\u2010\u03baB activation in C2C12 myotubes (PK\u20101: 3.1\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; KLM\u20101: 2.1\u2010fold, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.01), <jats:italic>Atrogin\u20101\/MAFbx<\/jats:italic> and <jats:italic>MuRF1<\/jats:italic> mRNA were only minimally and inconsistently upregulated by the CM of pancreatic cancer cell lines. Similarly, E3\u2010ubiquitin ligases and <jats:italic>REDD1<\/jats:italic> mRNA expression in myotubes were not altered by exposure to pancreatic tumour organoid CM. Compared with the control condition, CM from both PANCO\u20109a and PANCO\u201012a tumour organoids increased proliferation of myoblasts, which was accompanied by significant downregulation of the satellite cell marker paired\u2010box 7 (<jats:italic>PAX7<\/jats:italic>) (PANCO\u20109a: \u22122.1\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; PANCO\u201012a: \u22122.0\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) and myogenic factor 5 (<jats:italic>MYF5)<\/jats:italic> (PANCO\u20109a: \u22122.1\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001; PANCO\u201012a: \u22121.8\u2010fold, <jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.001) after 48\u00a0h of differentiation. Live cell imaging revealed accelerated alignment and fusion of myoblasts exposed to CM from PANCO\u20109a and PANCO\u201012a, which was in line with significantly increased <jats:italic>Myomaker<\/jats:italic> mRNA expression levels (PANCO\u20109a: 2.4\u2010fold, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.001; PANCO\u201012a: 2.2\u2010fold, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.004). These morphological and transcriptional alterations were accompanied by increased expression of muscle differentiation markers such as MyHC\u2010IIB (PANCO\u20109a: 2.5\u2010fold, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.04; PANCO\u201012a: 3.1\u2010fold, <jats:italic>P<\/jats:italic>\u00a0=\u00a00.006). Although the impact of organoid CM on myogenesis was not associated with the cachexia phenotype of the donor patients, it was specific for tumour organoids, as CM of control pancreas organoids did not modulate myogenic fusion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These data show that pancreatic tumour organoid\u2010derived factors alter the kinetics of myogenesis, which may eventually contribute to impaired muscle mass maintenance in cancer cachexia.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12917","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T08:55:11Z","timestamp":1644569711000},"page":"1302-1313","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Human pancreatic tumour organoid\u2010derived factors enhance myogenic differentiation"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6812-2897","authenticated-orcid":false,"given":"Rianne D.W.","family":"Vaes","sequence":"first","affiliation":[{"name":"Department of Surgery and NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David P.J.","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Surgery and NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elham A\u00efda","family":"Farshadi","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine Erasmus University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5202-9345","authenticated-orcid":false,"given":"Steven W.M.","family":"Olde Damink","sequence":"additional","affiliation":[{"name":"Department of Surgery and NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University  Maastricht The Netherlands"},{"name":"Department of General, Visceral and Transplantation Surgery RWTH Aachen University Hospital  Aachen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5054-8400","authenticated-orcid":false,"given":"Sander S.","family":"Rensen","sequence":"additional","affiliation":[{"name":"Department of Surgery and NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon C.","family":"Langen","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine and NUTRIM School of Nutrition and Translational Research in Metabolism Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,11]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21492"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.22"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(10)70218-7"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11121863"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.13593"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/MPA.0000000000001124"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00738"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12346"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00726-x"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6602165"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.10.004"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.09.027"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13539-014-0141-2"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0205467"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013604"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0054-2"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.07.016"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1186\/2049-3002-2-18"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2014.10.037"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.079509"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0409-3"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.12.021"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.05.082"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.039347"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12627"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910150505"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1620\/tjem.143.33"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02787375"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.00-0463"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp045"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00204.2014"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12915-018-0525-4"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.3945\/jn.114.207621"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2019.07.010"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI68523"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2017.11.006"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.03.044"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12079-018-0477-z"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.23893"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.292"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-02347-2"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.113.058388"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00310.2019"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2014.00001"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a008342"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.111.6.769"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2015.09.009"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00154.2002"},{"key":"e_1_2_8_51_1","first-page":"611","article-title":"Skeletal 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