IL-6; cancer associated fibroblasts; epithelial-to-mesenchymal transition; head and neck squamous cell carcinoma; radioresistance
Résumé :
[en] [en] BACKGROUND: Cancer-associated fibroblasts have been reported to play a central role in driving cancer progression, promoting metastasis, and conferring resistance to therapy in HNSCC.
METHODS: Indirect and direct co-culture models of HPV-positive and HPV-negative HNSCC cells with fibroblasts were developed to study the effect of fibroblasts on cancer cells. ELISA was used to measure IL-6 secretion in these models. To dissect the underlying signalling mechanisms, the effects of IL-6, an IL-6 receptor (IL-6R) inhibitor, a MAPK/ERK inhibitor, and a JAK/STAT inhibitor were evaluated. Epithelial-to-mesenchymal transition (EMT) was assessed by measuring EMT markers and conducting scratch assays and spheroid assays. Radioresistance was evaluated using clonogenic assays. Additionally, radioresistant (RR) cell lines were established from parental cells to examine the correlation between radioresistance and EMT.
RESULTS: Fibroblasts were found to drive EMT-like changes and heightened radioresistance in HNSCC cells through IL-6 secretion. Remarkably, these Fb-driven effects were robustly reversed using IL-6R and MAPK/ERK inhibitors in both HPV-positive and HPV-negative cell lines, whereas JAK/STAT inhibitors proved effective only in HPV-negative cells. RR cell lines exhibit a more aggressive phenotype than their parental counterparts, marked by pronounced EMT features and heightened resistance to radiotherapy. Importantly, these aggressive characteristics were substantially attenuated by targeting IL-6R or MAPK/ERK pathways.
CONCLUSIONS: This study highlights the critical role of fibroblast-secreted IL-6 in driving and maintaining EMT and radioresistance in HNSCC, resulting in a more aggressive tumour phenotype. Targeting the IL-6/IL-6R/ERK pathway emerges as a promising therapeutic approach for combating CAF-driven tumour progression and improving clinical outcomes in patients with aggressive, therapy-resistant HNSCC.
Disciplines :
Sciences du vivant: Multidisciplinaire, généralités & autres
Auteur, co-auteur :
Li, Xinyang; Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King's College London, Hodgkin Building, London SE1 1UL, UK
ESCOFFIER, Hugues ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
SAUTER, Thomas ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Tavassoli, Mahvash ; Head and Neck Oncology Group, Centre for Host Microbiome Interaction, King's College London, Hodgkin Building, London SE1 1UL, UK
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Targeting Fibroblast-Derived Interleukin 6: A Strategy to Overcome Epithelial-Mesenchymal Transition and Radioresistance in Head and Neck Cancer.
Joint PhD program between King’s College London and China Scholarship Council FNR - Luxembourg National Research Fund
N° du Fonds :
PRIDE21/16763386/CANBIO2
Subventionnement (détails) :
This work was supported by a joint PhD program between King’s College London and China Scholarship Council (2021-KCSC) and the Luxembourg National Research Fund (PRIDE21/16763386/CANBIO2).
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