RESUMEN
Drug tolerant persister (DTP) cells enter into a reversible slow-cycling state after drug treatment. We performed proteomic characterization of the breast cancer (BC) DTP cell secretome after eribulin treatment. We showed that the growth differentiation factor 15 (GDF15) is a protein significantly over-secreted upon eribulin treatment. The biomarker potential of GDF15 was confirmed in 3D-cell culture models using BC cells lines and PDXs, as well as in a TNBC in vivo model. We also found that GDF15 is required for survival of DTP cells. Direct participation of GDF15 and its receptor GFRAL in eribulin-induction of DTPs was established by the enhanced cell killing of DTPs by eribulin seen under GDF15 and GFRAL loss of function assays. Finally, we showed that combination therapy of eribulin plus an anti-GDF15 antibody kills BC-DTP cells. Our results suggest that targeting GDF15 may help eradicate DTP cells and block the onset of acquired resistance.
RESUMEN
OBJECTIVE: Early lifestyle interventions in children with obesity decrease risk of obesity and metabolic disorders during adulthood. This study aimed to identify metabolic signatures associated with lifestyle intervention in urine samples from prepubertal children with obesity. METHODS: Thirty-four prepubertal children with obesity were studied before and after a 6-month lifestyle intervention program, and anthropometric, metabolic, and nutritional variables were collected. A nuclear magnetic resonance approach was applied to obtain the metabolomic profile from urine samples. Partial least squares-discriminant analysis (PLS-DA) was used to achieve group classification and variable importance on projection (VIP) for biomarker selection. RESULTS: The intervention reduced caloric intake by 10% (P < 0.05) and BMI standard deviation score by 0.47 SD (P < 0.001). PLS-DA identified trimethylamine N-oxide (TMAO, VIP = 2.21) as the metabolite with the highest discrimination properties between groups. Urine TMAO levels were reduced after the intervention (P < 0.05). TMAO is a biomarker of cardiovascular disease risk and is a product of gut microbiota-dependent metabolism of certain dietary compounds, including choline. Notably, changes in TMAO levels after the intervention did not correlate to differences in choline intake but were inversely associated with fiber intake (P < 0.05). CONCLUSIONS: These results indicate that lifestyle intervention decreases TMAO levels in children with obesity.
