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.

Expression of the microRNA-200 Family, microRNA-205, and Markers of Epithelial–Mesenchymal Transition as Predictors for Endoscopic Submucosal Dissection over Esophagectomy in Esophageal Adenocarcinoma: A Single-Center Experience

“…These data show that measurement of classical EMT markers might distinguish localized from regional EAC samples and are in line with recent reports that describe EMT and loss of epithelial markers as being involved in progression of esophageal carcinoma [20,[33][34][35]. As EMT and tumor invasion represent key criteria regarding the decision of ESD versus surgery, EMT-related factors might represent attractive markers to support the decision of ESD versus surgery.…”

Human Skin Keratinocytes on Sustained TGF-β Stimulation Reveal Partial EMT Features and Weaken Growth Arrest Responses

“…The AP-1 family includes c-Jun, whose results in this work were already discussed. Intriguingly, increased IL-6 levels have been linked to EMT responses in several epithelial cell models in the context of a senescent secretome [82][83][84][85][86]. Few reports describe the ability of TGF-β to promote IL-6 induction: In Tenon's capsule fibroblasts, IL-6 autocrine signaling, in response to TGF-β, was linked to alpha-Smooth Muscle Actin expression, myofibroblast transdifferentiating and scarring [87]; a similar loop has been reported in prostate epithelial carcinoma cell lines, for which a synergistic mechanism involving Smad2, NF-kappaB and MAP-Kinases was proposed [88].…”

Pleiotropic Effects of Epithelial Mesenchymal Crosstalk on Head and Neck Cancer: EMT and beyond

“…One of the major signalling factors in EMC is interleukin-6 (IL-6) [14][15][16]. IL-6 is a pleiotropic cytokine, widely appreciated as a major regulator of the acute phase response, yet harbouring numerous functions outside the immune system, including lipid metabolism, insulin resistance, mitochondrial function, and neuroendocrine regulation [16,17].…”

“…IL-6 is a pleiotropic cytokine, widely appreciated as a major regulator of the acute phase response, yet harbouring numerous functions outside the immune system, including lipid metabolism, insulin resistance, mitochondrial function, and neuroendocrine regulation [16,17]. IL-6 signaling is mediated by a heterodimeric receptor complex comprised of the ligand-binding subunit and the signaltransducing subunit [14]. IL-6 is one of the main chemokines present in serum samples of head and neck cancer patients and elevated IL-6 levels independently predict tumor recurrence, poor survival and tumor metastasis [18].…”