Targeting the CAF-GDF15 axis attenuates AKT-mediated mitochondrial rewiring and chemoradiation resistance in esophageal adenocarcinoma.

backgroundTherapeutic resistance in esophageal adenocarcinoma (EAC) remains poorly understood at the level of tumor-stroma interactions. We investigated whether cancer-associated fibroblast (CAF)-derived signaling contributes to chemoradiation resistance and adverse clinical outcomes in EAC, with a focus on the functional role of GDF15 within the CAF-secreted program.

methodsSerum GDF15 levels were analyzed in EAC patients before and after neoadjuvant chemoradiotherapy according to the CROSS regimen, with prognostic relevance validated in an independent cohort and public datasets. Primary EAC CAFs, EAC cell lines, and patient-derived organoids (PDOs) were used to model tumor-stroma crosstalk in 2D and 3D co-culture systems. Compartment-specific transcriptomic and proteomic profiling identified CAF-regulated pathways. Genetic depletion and antibody-mediated neutralization of GDF15 were used to assess its functional contribution, followed by evaluation of chemoradiation sensitivity, mitochondrial function, oxidative phosphorylation dependency, and AKT pathway activation.

resultsSerum GDF15 levels increased significantly following CROSS treatment, and elevated post-treatment GDF15 independently predicted poor overall survival in EAC patients. CAFs enhanced resistance to chemotherapy and radiotherapy in EAC cells and PDOs, accompanied by increased GDF15 secretion. Compartment-specific transcriptomic analysis and ELISA supported CAFs as a major source of inducible GDF15 during tumor-stroma interaction. Genetic depletion of GDF15 reduced treatment resistance, whereas recombinant GDF15 partially restored chemoresistance in GDF15-depleted models. GDF15 neutralization attenuated CAF-associated cisplatin tolerance. Mechanistically, GDF15 contributed to AKT activation and mitochondrial respiratory adaptation, including enhanced oxidative phosphorylation. Pharmacological attenuation of oxidative phosphorylation further sensitized EAC cells to cisplatin, particularly under CAF co-culture conditions.

conclusionsOur study identifies CAF-derived GDF15 as a clinically relevant and functionally targetable component of a broader CAF-secreted resistance program in EAC. GDF15 contributes to AKT-associated mitochondrial adaptation and tumor cell tolerance to chemoradiation, while elevated post-CROSS serum GDF15 serves as a prognostic biomarker. These findings support further investigation of GDF15-directed and mitochondria-targeted strategies to overcome CAF-associated treatment resistance in esophageal adenocarcinoma.