Abstract
Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are linked to weight loss in non-small cell lung cancer (NSCLC) patients. This study examines the role of the integrated stress response (ISR) cytokine growth differentiation factor 15 (GDF15) in regulating cachexia using patient-derived and engineered STK11/LKB1-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing GDF15 from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type STK11/LKB1 in NSCLC lines with endogenous STK11/LKB1 loss reverses the ISR and reduces GDF15 expression rescuing the cachexia phenotype. Collectively, these findings implicate tumor-derived GDF15 as a key mediator and therapeutic target in STK11/LKB1-mutant NSCLC-associated cachexia.
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Acknowledgements
We thank Michael Brown, Joseph Goldstein, Shawn Burgess, and Jay Horton for their suggestions and review. We also thank Bei Zhang (Pfizer), Mingjian Lu (Pfizer), Junjie Li (Pfizer), Ja Young Kim-Mueller (Pfizer) and Danna Breen (Pfizer) for their contributions. We thank Natalie Lopez and Min Ding for their excellent technical assistance. This work was supported by grants from the Burroughs Wellcome Fund Career Awards for Medical Scientists (1019692, R.E.I.); American Cancer Society Grant (133889-RSG-19-195-01-TBE, R.E.I.); Cancer Prevention and Research Institute of Texas (RP230140 (R.E.I./P.I.) and RP210041 (E.A.A.)); and National Institutes of Health grants (1R01CA266900 (R.E.I./P.I.), 1R01CA258684 (J.K.), 1R01DK128166 (R.E.I./P.I.), 1P30DK127984 (R.E.I.), P30CA142543 (J.D.M., J.K., R.E.I.), P50CA070907 (J.D.M., J.K., R.E.I.), and T32DK007745 (E.L.)).
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J.Y., T.G., A.G., N.W., E.L., J.K., B.A.R., P.I., and R.E.I. designed experiments. J.Y., T.G., A.G., N.W., E.L., D.Z., S.S., T.S., and J.M.S. conducted experiments and analyzed the data. Q.D., E.A.A., and J.D.M. provided reagents. B.M.E., Z.W., I.T., E.P., J.D.M., P.I. and R.E.I. analyzed data. J.Y. performed statistical analysis. J.Y., P.I., and R.E.I. wrote the manuscript. All authors reviewed and revised the manuscript.
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All authors acknowledge no conflicts of interest related to this work except R.E.I. who maintains collaborative cancer cachexia research projects with Pfizer, Inc. and J.D.M. who receives royalties from the National Institute of Health and University of Texas Southwestern Medical Center for distribution of human tumor cell lines.
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Nature Communications thanks Fabio Penna, who co-reviewed with Giacomo Rubini, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
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Yu, J., Guo, T., Gupta, A. et al. Cancer cachexia in STK11/LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68702-y
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DOI: https://doi.org/10.1038/s41467-026-68702-y
