Cancer cachexia in STK11 and LKB1-mutated non-small cell lung cancer is dependent on tumor-secreted GDF15

Authors
Yu, Jinhai, Guo, Tong, Gupta, Arun, Llano, Ernesto M., Salisbury, Thomas, Wajahat, Naureen, Zhao, Dianne, Slater, Sean, Deng, Qing, Akbay, Esra A., Rothermel, Beverly A., Shelton, John M., Evers, Bret M., Wu, Zhidan, Tzameli, Iphigenia, Pashos, Evanthia, Kim, James, Minna, John D., Iyengar, Puneeth, Infante, Rodney E.


Lab

Journal
Nature Communications

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. GDF15 has been associated with cancer-associated cachexia. Here, the authors show that STK11/LKB1 loss-of-function mutations in non-small cell lung cancer result in an exaggerated integrated stress response culminating in the tumor cell secretion of the cytokine GDF15 promoting cachexia.

Keywords/Topics
Cancer metabolism; Mechanisms of disease; Non-small-cell lung cancer

BIOSEB Instruments Used:
Grip strength test (BIO-GS4)

Source :

https://www.nature.com/articles/s41467-026-68702-y

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