Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Ebbing EA

PROVIDER: S-EPMC6369811 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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

Ebbing Eva A EA van der Zalm Amber P AP Steins Anne A Creemers Aafke A Hermsen Simone S Rentenaar Rosa R Klein Michelle M Waasdorp Cynthia C Hooijer Gerrit K J GKJ Meijer Sybren L SL Krishnadath Kausilia K KK Punt Cornelis J A CJA van Berge Henegouwen Mark I MI Gisbertz Suzanne S SS van Delden Otto M OM Hulshof Maarten C C M MCCM Medema Jan Paul JP van Laarhoven Hanneke W M HWM Bijlsma Maarten F MF

Proceedings of the National Academy of Sciences of the United States of America 20190122 6

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 st ...[more]

PMID: 30670657

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Dataset Information

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

Publications

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

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