Cancer Cachexia in STK11/LKB1-mutated NSCLC is Dependent on Tumor-secreted GDF15

Abstract

ABSTRACTCachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations inSTK11/LKB1, 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 engineeredSTK11/LKB1-mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derivedSTK11/LKB1-mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derivedSTK11/LKB1-mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing ofGDF15in multiple human NSCLC lines was also sufficient to eliminatein vivocirculating 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-typeSTK11/LKB1in a humanSTK11/LKB1loss-of-function NSCLC line that normally induces cachexiain vivocorrelated 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 withSTK11/LKB1loss-of-function mutations promote cachexia-associated wasting.