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

Eva A. Ebbing, Amber P. van der Zalm, Anne Steins, Aafke Creemers, Simone Hermsen, Rosa Rentenaar, Michelle Klein, Cynthia Waasdorp, Gerrit K. J. Hooijer, Sybren L. Meijer, Kausilia K. Krishnadath, Cornelis J. A. Punt, Mark I. van Berge Henegouwen, Suzanne S. Gisbertz, Otto M. van Delden, Maarten C. C. M. Hulshof, Jan Paul Medema, Hanneke W. M. van Laarhoven, Maarten F. Bijlsma

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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.
Original languageEnglish
Pages (from-to)2237-2242
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
Publication statusPublished - 5 Feb 2019
Externally publishedYes

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