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

Jinhai Yu1,2,3, Tong Guo1, Arun Gupta1

  • 1Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Nature Communications
|January 30, 2026
PubMed

Insights

Tumor-secreted GDF15 drives cancer cachexia in STK11/LKB1-mutant NSCLC. Neutralizing GDF15 or restoring STK11/LKB1 function reverses this wasting syndrome, offering new therapeutic targets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Syndrome

Background:

  • Cancer cachexia is a complex wasting syndrome characterized by loss of adipose tissue and muscle mass, significantly impacting cancer patient outcomes.
  • Loss-of-function mutations in STK11/LKB1, a key regulator of AMP-activated protein kinase, are implicated in cancer cachexia (CC) and weight loss in non-small cell lung cancer (NSCLC).
  • The integrated stress response (ISR) pathway and its mediator, growth differentiation factor 15 (GDF15), are increasingly recognized for their roles in cancer progression and cachexia.

Purpose of the Study:

  • To investigate the role of tumor-derived GDF15 in mediating cachexia associated with STK11/LKB1-mutant NSCLC.
  • To explore GDF15 as a potential therapeutic target for counteracting cancer cachexia.

Main Methods:

  • Utilized patient-derived and engineered STK11/LKB1-mutant NSCLC cell lines.
  • Measured serum GDF15 levels in preclinical models bearing these tumors.
  • Administered GDF15-neutralizing antibodies and employed gene silencing techniques to assess GDF15's impact.
  • Restored wild-type STK11/LKB1 function in mutant NSCLC lines to observe phenotypic rescue.

Main Results:

  • Elevated serum GDF15 levels were observed in mice with STK11/LKB1-mutant NSCLC.
  • Neutralization of GDF15 or its silencing in tumor cells prevented adipose and muscle loss, decreased strength, and mitigated weight reduction.
  • Restoration of wild-type STK11/LKB1 reversed the ISR, reduced GDF15 expression, and rescued the cachexia phenotype.
  • These findings confirm tumor cells as the primary source of GDF15 driving cachexia.

Conclusions:

  • Tumor-derived GDF15 is a critical mediator of cachexia in STK11/LKB1-mutant NSCLC.
  • Targeting GDF15 presents a promising therapeutic strategy for managing cancer cachexia in this patient population.

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