TY - JOUR
T1 - Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma
AU - Ebbing, Eva A.
AU - van der Zalm, Amber P.
AU - Steins, Anne
AU - Creemers, Aafke
AU - Hermsen, Simone
AU - Rentenaar, Rosa
AU - Klein, Michelle
AU - Waasdorp, Cynthia
AU - Hooijer, Gerrit K. J.
AU - Meijer, Sybren L.
AU - Krishnadath, Kausilia K.
AU - Punt, Cornelis J. A.
AU - van Berge Henegouwen, Mark I.
AU - Gisbertz, Suzanne S.
AU - van Delden, Otto M.
AU - Hulshof, Maarten C. C. M.
AU - Medema, Jan Paul
AU - van Laarhoven, Hanneke W. M.
AU - Bijlsma, Maarten F.
PY - 2019/2/5
Y1 - 2019/2/5
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85061152076&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30670657
U2 - 10.1073/pnas.1820459116
DO - 10.1073/pnas.1820459116
M3 - Article
C2 - 30670657
VL - 116
SP - 2237
EP - 2242
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 6
ER -