{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T02:15:55Z","timestamp":1772676955477,"version":"3.50.1"},"posted":{"date-parts":[[2024,6,17]]},"group-title":"Cancer Biology","reference-count":32,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,17]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Cachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in\n                  <jats:italic>STK11\/LKB1<\/jats:italic>\n                  , a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered\n                  <jats:italic>STK11\/LKB1<\/jats:italic>\n                  -mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derived\n                  <jats:italic>STK11\/LKB1<\/jats:italic>\n                  -mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derived\n                  <jats:italic>STK11\/LKB1<\/jats:italic>\n                  -mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing of\n                  <jats:italic>GDF15<\/jats:italic>\n                  in multiple human NSCLC lines was also sufficient to eliminate\n                  <jats:italic>in vivo<\/jats:italic>\n                  circulating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-type\n                  <jats:italic>STK11\/LKB1<\/jats:italic>\n                  in a human\n                  <jats:italic>STK11\/LKB1<\/jats:italic>\n                  loss-of-function NSCLC line that normally induces cachexia\n                  <jats:italic>in vivo<\/jats:italic>\n                  correlated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs with\n                  <jats:italic>STK11\/LKB1<\/jats:italic>\n                  loss-of-function mutations promote cachexia-associated wasting.\n                <\/jats:p>","DOI":"10.1101\/2024.06.14.598891","type":"posted-content","created":{"date-parts":[[2024,6,17]],"date-time":"2024-06-17T17:20:15Z","timestamp":1718644815000},"source":"Crossref","is-referenced-by-count":1,"title":["<i>Cancer Cachexia in STK11\/LKB1<\/i>\n                  -mutated NSCLC is Dependent on Tumor-secreted GDF15"],"prefix":"10.64898","author":[{"given":"Jinhai","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arun","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ernesto M.","family":"Llano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naureen","family":"Wajahat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sean","family":"Slater","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Esra A.","family":"Akbay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John M.","family":"Shelton","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bret M.","family":"Evers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhidan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iphigenia","family":"Tzameli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evanthia","family":"Pashos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John D.","family":"Minna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Puneeth","family":"Iyengar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodney E.","family":"Infante","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024062203150571000_2024.06.14.598891v1.1","doi-asserted-by":"crossref","unstructured":"Iyengar P , Gandhi AY , Granados J , et al. 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