{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T21:20:11Z","timestamp":1792704011677,"version":"4.5.0"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"34","license":[{"start":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T00:00:00Z","timestamp":1692144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["AR66696"],"award-info":[{"award-number":["AR66696"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"HHS | NIH | National Cancer Institute","doi-asserted-by":"publisher","award":["CA102701"],"award-info":[{"award-number":["CA102701"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000043","name":"American Association for Cancer Research","doi-asserted-by":"publisher","award":["17-20-25-DOLE"],"award-info":[{"award-number":["17-20-25-DOLE"]}],"id":[{"id":"10.13039\/100000043","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,8,22]]},"abstract":"<jats:p>\n                    Cancer cachexia, and its associated complications, represent a large and currently untreatable roadblock to effective cancer management. Many potential therapies have been proposed and tested\u2014including appetite stimulants, targeted cytokine blockers, and nutritional supplementation\u2014yet highly effective therapies are lacking. Innovative approaches to treating cancer cachexia are needed. Members of the Kruppel-like factor (KLF) family play wide-ranging and important roles in the development, maintenance, and metabolism of skeletal muscle. Within the KLF family, we identified KLF10 upregulation in a multitude of wasting contexts\u2014including in pancreatic, lung, and colon cancer mouse models as well as in human patients. We subsequently interrogated loss-of-function of KLF10 as a potential strategy to mitigate cancer associated muscle wasting. In vivo studies leveraging orthotopic implantation of pancreas cancer cells into wild-type and KLF10 KO mice revealed significant preservation of lean mass and robust suppression of pro-atrophy muscle-specific ubiquitin ligases Trim63 and Fbxo32, as well as other factors implicated in atrophy, calcium signaling, and autophagy. Bioinformatics analyses identified Transforming growth factor beta (TGF-\u03b2), a known inducer of KLF10 and cachexia promoting factor, as a key upstream regulator of KLF10. We provide direct in vivo evidence that KLF10 KO mice are resistant to the atrophic effects of TGF-\u03b2. ChIP-based binding studies demonstrated direct binding to\n                    <jats:italic>Trim63<\/jats:italic>\n                    , a known wasting-associated atrogene. Taken together, we report a critical role for the TGF-\u03b2\/KLF10 axis in the etiology of pancreatic cancer\u2013associated muscle wasting and highlight the utility of targeting KLF10 as a strategy to prevent muscle wasting and limit cancer-associated cachexia.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2215095120","type":"journal-article","created":{"date-parts":[[2023,8,16]],"date-time":"2023-08-16T13:44:30Z","timestamp":1692193470000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":33,"title":["A TGF-\u03b2\/KLF10 signaling axis regulates atrophy-associated genes to induce muscle wasting in pancreatic cancer"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7479-1149","authenticated-orcid":false,"given":"Aneesha","family":"Dasgupta","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905"},{"name":"Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202"},{"name":"Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202"},{"name":"Tumor Microenvironment &amp; Metastasis Program, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel F.","family":"Gibbard","sequence":"additional","affiliation":[{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca E.","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905"},{"name":"Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202"},{"name":"Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202"},{"name":"Tumor Microenvironment &amp; Metastasis Program, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2706-9652","authenticated-orcid":false,"given":"Paige C.","family":"Arneson-Wissink","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905"},{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7372-1894","authenticated-orcid":false,"given":"Alexandra M.","family":"Ducharme","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7938-438X","authenticated-orcid":false,"given":"Elizabeth S.","family":"Bruinsma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3406-470X","authenticated-orcid":false,"given":"John R.","family":"Hawse","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905"},{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aminah","family":"Jatoi","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason D.","family":"Doles","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905"},{"name":"Department of Anatomy, Cell Biology, and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202"},{"name":"Indiana Center for Musculoskeletal Health, Indianapolis, IN 46202"},{"name":"Tumor Microenvironment &amp; Metastasis Program, Indiana University Simon Comprehensive Cancer Center, Indianapolis, IN 46202"},{"name":"Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, MN 55905"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,8,16]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0149-2918(05)80001-3"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11605-008-0505-z"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2017.105"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132786"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1620013114"},{"key":"e_1_3_4_6_2","first-page":"512","article-title":"The effect of blocking TNF-alpha in patients with cancer-related cachexia and anorexia","volume":"149","author":"Gueta I.","year":"2010","unstructured":"I. Gueta, A. Altman, Y. Shoenfeld, The effect of blocking TNF-alpha in patients with cancer-related cachexia and anorexia. Harefuah 149, 512\u2013514, 551, 550 (2010).","journal-title":"Harefuah"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12331"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00069"},{"key":"e_1_3_4_9_2","doi-asserted-by":"crossref","unstructured":"L. Fan Muscle Kruppel-like factor 15 regulates lipid flux and systemic metabolic homeostasis. J. Clin. Invest. 131 e139496 (2021). e139496","DOI":"10.1172\/JCI139496"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2011.01.001"},{"key":"e_1_3_4_11_2","doi-asserted-by":"crossref","unstructured":"Y. Hirata Hyperglycemia induces skeletal muscle atrophy via a WWP1\/KLF15 axis. JCI Insight 4 e124952 (2019). e124952","DOI":"10.1172\/jci.insight.124952"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/23.23.4907"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10299"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0164566"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1205681"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22434"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.457648"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2017.09.001"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-3-7"},{"key":"e_1_3_4_20_2","doi-asserted-by":"crossref","unstructured":"S. Hayashi I. Manabe Y. Suzuki F. Relaix Y. Oishi Klf5 regulates muscle differentiation by directly targeting muscle-specific genes in cooperation with MyoD in mice. Elife 5 e17462 (2016). e17462","DOI":"10.7554\/eLife.17462"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-011-1186-6"},{"key":"e_1_3_4_22_2","doi-asserted-by":"crossref","unstructured":"A. Dasgupta Anticachectic regulator analysis reveals Perp-dependent antitumorigenic properties of 3-methyladenine in pancreatic cancer. JCI Insight 7 e153842 (2022). e153842","DOI":"10.1172\/jci.insight.153842"},{"key":"e_1_3_4_23_2","doi-asserted-by":"crossref","unstructured":"J. E. Rupert Tumor-derived IL-6 and trans-signaling among tumor fat and muscle mediate pancreatic cancer cachexia. J. Exp. Med. 218 e20190450 (2021). e20190450","DOI":"10.1084\/jem.20190450"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13395-020-00225-6"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714703115"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13081975"},{"key":"e_1_3_4_27_2","unstructured":"A. Dasgupta KLF10 WT and KO tumor-bearing mice muscles. Sequence Read Archive (SRA). https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA988245. Deposited 27 June 2023."},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aay9592"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2992-16.2016"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba3458"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109971"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1186\/rr67"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00235"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-16-2589"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers10060161"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.12.021"},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","unstructured":"A. Dasgupta SIRT1-NOX4 signaling axis regulates cancer cachexia. J. Exp. Med. 217 e20190745 (2020). e20190745","DOI":"10.1084\/jem.20190745"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3390\/metabo8040061"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2089"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1152\/japplphysiol.00762.2017"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.13214"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2215095120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T09:38:44Z","timestamp":1695289124000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2215095120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,16]]},"references-count":41,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2023,8,22]]}},"alternative-id":["10.1073\/pnas.2215095120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2215095120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,16]]},"assertion":[{"value":"2022-09-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-16","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2215095120"}}