Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 6; pp. 2237 - 2242
• Main Authors: Ebbing, Eva A., van der Zalm, Amber P., Steins, Anne, Creemers, Aafke, Hermsen, Simone, Rentenaar, Rosa, Klein, Michelle, Waasdorp, Cynthia, Hooijer, Gerrit K. J., Meijer, Sybren L., Krishnadath, Kausilia K., Punt, Cornelis J. A., van Berge Henegouwen, Mark I., Gisbertz, Suzanne S., van Delden, Otto M., Hulshof, Maarten C. C. M., Medema, Jan Paul, van Laarhoven, Hanneke W. M., Bijlsma, Maarten F.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.02.2019
• Subjects: Adenocarcinoma; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - therapy; Animals; Antineoplastic Agents - pharmacology; Biological Sciences; Cancer; Cancer therapies; Cancer-Associated Fibroblasts - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - radiation effects; Chemoradiotherapy; Disease Models, Animal; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophageal Neoplasms - therapy; Esophagus; Fibroblasts; Gene expression; Humans; Interleukin 6; Interleukin-6 - metabolism; Medical prognosis; Mesenchyme; Mice; Organoids; Patients; Radiation Tolerance; Sensitivity analysis; Serum levels; Stromal Cells - metabolism; Therapy; Tissue Culture Techniques; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; tumor stroma; esophageal adenocarcinoma; IL-6; epithelial-to-mesenchymal transition; therapy resistance
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1820459116

Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6–producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.