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<p>Cachexia is a wasting syndrome involving adipose, muscle, and body weight loss in cancer patients. Tumor loss-of-function mutations in <i>STK11</i>/<i>LKB1</i>, 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 <i>STK11/LKB1</i>-mutant NSCLC lines. Tumor cell-derived serum GDF15 levels are elevated in mice bearing these tumors. Treatment with a GDF15-neutralizing antibody or silencing <i>GDF15</i> from tumor cells prevents adipose/muscle loss, strength decline, and weight reduction, identifying tumors cells as the GDF15 source. Restoring wild-type <i>STK11/LKB1</i> 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 <i>STK11/LKB1</i>-mutant NSCLC-associated cachexia.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月30日

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

摘要

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.