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-beta) of EAC cells. Inhibition of TGF-beta ligands effectively abolished chemoradiation-induced EMT. Assessment of TGF-beta 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-beta production. Monitoring TGF-beta serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF-beta targeting therapy.