Stromal-derived interleukin 6 drives epithelial-to-mesenchymal transition and therapy resistance in esophageal adenocarcinoma.
Eva A EbbingAmber P van der ZalmAnne SteinsAafke CreemersSimone HermsenRosa RentenaarMichelle KleinCynthia WaasdorpGerrit K J HooijerSybren L MeijerKausilia K KrishnadathCornelis J A PuntMark I van Berge HenegouwenSuzanne S GisbertzOtto M van DeldenMaarten C C M HulshofJan Paul MedemaHanneke W M van LaarhovenMaarten F BijlsmaPublished in: Proceedings of the National Academy of Sciences of the United States of America (2019)
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.
Keyphrases
- bone marrow
- locally advanced
- rectal cancer
- squamous cell carcinoma
- end stage renal disease
- emergency department
- newly diagnosed
- chronic kidney disease
- ejection fraction
- radiation therapy
- cancer therapy
- mesenchymal stem cells
- genome wide
- dna methylation
- replacement therapy
- drug induced
- endothelial cells
- high glucose
- chemotherapy induced