{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:28:22Z","timestamp":1785403702078,"version":"3.56.0"},"reference-count":92,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nutricia Research"},{"id":[{"id":"https:\/\/ror.org\/04yx5fa32","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Cancer-associated cachexia (CAC) can affect up to 80% of patients with late-stage cancer and is characterized by depletion of skeletal muscle mass with or without loss of fat tissue. No effective treatments are currently available, and reversing CAC requires understanding the intracellular processes of muscle atrophy and its cancer-related extracellular triggers. In this study, we aimed to disentangle tumor- and host-driven mechanisms in CAC muscle wasting. Methods: In skeletal muscle tissue obtained from control non-tumor-bearing mice and cachectic mice resulting from orthotopically implanted 344P lung adenocarcinoma cells, transcriptomic analyses were performed to identify muscle wasting-associated processes. To explore whether these reflected direct tumor-induced effects, 344P tumor-conditioned medium (tCM) was applied to in vitro cultured C2C12 skeletal muscle cells to investigate the impact on muscle proteolysis, myogenesis and mitochondrial function. Results: RNAseq data revealed increased proteolysis along with decreased myogenesis-related processes, and prominent downregulation of genes encoding mitochondrial OXPHOS complexes, in cachectic mouse muscle. Exposure of cultured skeletal muscle cells to tCM reduced mitochondrial respiration and induced changes in mitochondrial mass and mitochondrial DNA copy number. tCM did not induce myotube atrophy, or activation of proteolysis-related signaling, in fully differentiated myotubes. In contrast, tCM reversibly inhibited myoblast\u2013myotube fusion, and reduced myogenic and muscle-specific gene expression in differentiating myoblasts. Application of CCCP to simulate muscle mitochondrial dysfunction reproduced the myogenesis-impairing phenotype caused by tCM. Conclusions: Our results show that factors present in the cachexia-inducing lung tumor secretome directly impair myogenesis and muscle mitochondrial function, whereas activation of muscle catabolic processes requires host-dependent mechanisms.<\/jats:p>","DOI":"10.3390\/cancers18132130","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:50:37Z","timestamp":1782867037000},"page":"2130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Secretome of a Cachexia-Inducing Lung Tumor Impairs Mitochondrial Function and Skeletal Muscle Differentiation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7909-1344","authenticated-orcid":false,"given":"Nikki","family":"Wanders","sequence":"first","affiliation":[{"name":"Department of Translational Genomics, Mental Health and Neurosciences Research Institute (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2230-0840","authenticated-orcid":false,"given":"Marvin","family":"Martens","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Kelders","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Manse","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"van Krimpen","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Groenen","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5549-6731","authenticated-orcid":false,"given":"Chrysi","family":"Kapsali","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Mental Health and Neurosciences Research Institute (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Bilbao Fraile","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantina","family":"Bermperi","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niels","family":"Boumans","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssra","family":"Ahidar","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8887-4137","authenticated-orcid":false,"given":"Ludwig","family":"Dubois","sequence":"additional","affiliation":[{"name":"The M-Lab, Department of Precision Medicine, Research Institute for Oncology and Reproduction (GROW), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands"},{"name":"Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hubert","family":"Smeets","sequence":"additional","affiliation":[{"name":"Department of Translational Genomics, Mental Health and Neurosciences Research Institute (MHeNS), Maastricht University, Universiteitssingel 40, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"van de Worp","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8622-3058","authenticated-orcid":false,"given":"Ramon","family":"Langen","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Research Institute of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.21037\/apm.2018.12.01","article-title":"Cancer cachexia is defined by an ongoing loss of skeletal muscle 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