Chemoradiation induces epithelial‐to‐mesenchymal transition in esophageal adenocarcinoma

Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplatin, paclitaxel and radiotherapy. We developed an in vitro approximation of this regimen and applied it to primary patient‐derived cultures. We observed a heterogeneous epithelial‐to‐mesenchymal (EMT) response to the high therapeutic pressure exerted by chemoradiation. We found EMT to be initiated by the autocrine production and response to transforming growth factor beta (TGF‐β) of EAC cells. Inhibition of TGF‐β ligands effectively abolished chemoradiation‐induced EMT. Assessment of TGF‐β serum levels in EAC patients revealed that high levels after neoadjuvant treatment predicted the presence of fluorodeoxyglucose uptake in lymph nodes on the post‐chemoradiation positron emission tomography‐scan. Our study shows that chemoradiation contributes to resistant metastatic disease in EAC patients by inducing EMT via autocrine TGF‐β production. Monitoring TGF‐β serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF‐β targeting therapy. What's new? Therapeutic resistance and disease recurrence are major setbacks affecting the survival of patients with esophageal adenocarcinoma (EAC). Resistance mechanisms in EAC, however, await elucidation. Here, epithelial‐to‐mesenchymal transition (EMT), a hallmark of invasive tumor phenotype, was investigated as a possible mechanism driving chemoradiation resistance in EAC. In EAC cells, chemoradiation was found to induce EMT, a process mediated via autocrine TGF‐β production. Inhibition of TGF‐β counteracted this process. In patients, elevated circulating TGF‐β levels post‐chemoradiation were associated with progressive disease. Together, these data suggest that TGF‐β is a useful marker for identifying patients who might benefit from TGF‐β inhibition during chemoradiation.