Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction
(1) Background: Epiregulin (EREG) is a ligand of EGFR and ErB4 involved in the development and the progression of various cancers including head and neck squamous cell carcinoma (HNSCC). Its overexpression in HNSCC is correlated with short overall survival and progression-free survival but predictiv...
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| Format: | Article |
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MDPI AG
2023-02-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/5/733 |
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| author | Aude Jehl Ombline Conrad Mickaël Burgy Sophie Foppolo Romain Vauchelles Carole Ronzani Nelly Etienne-Selloum Marie-Pierre Chenard Aurélien Danic Thomas Dourlhes Claire Thibault Philippe Schultz Monique Dontenwill Sophie Martin |
| author_facet | Aude Jehl Ombline Conrad Mickaël Burgy Sophie Foppolo Romain Vauchelles Carole Ronzani Nelly Etienne-Selloum Marie-Pierre Chenard Aurélien Danic Thomas Dourlhes Claire Thibault Philippe Schultz Monique Dontenwill Sophie Martin |
| author_sort | Aude Jehl |
| collection | DOAJ |
| description | (1) Background: Epiregulin (EREG) is a ligand of EGFR and ErB4 involved in the development and the progression of various cancers including head and neck squamous cell carcinoma (HNSCC). Its overexpression in HNSCC is correlated with short overall survival and progression-free survival but predictive of tumors responding to anti-EGFR therapies. Besides tumor cells, macrophages and cancer-associated fibroblasts shed EREG in the tumor microenvironment to support tumor progression and to promote therapy resistance. Although EREG seems to be an interesting therapeutic target, no study has been conducted so far on the consequences of EREG invalidation regarding the behavior and response of HNSCC to anti-EGFR therapies and, more specifically, to cetuximab (CTX); (2) Methods: EREG was silenced in various HNSCC cell lines. The resulting phenotype (growth, clonogenic survival, apoptosis, metabolism, ferroptosis) was assessed in the absence or presence of CTX. The data were confirmed in patient-derived tumoroids; (3) Results: Here, we show that EREG invalidation sensitizes cells to CTX. This is illustrated by the reduction in cell survival, the alteration of cell metabolism associated with mitochondrial dysfunction and the initiation of ferroptosis characterized by lipid peroxidation, iron accumulation and the loss of GPX4. Combining ferroptosis inducers (RSL3 and metformin) with CTX drastically reduces the survival of HNSCC cells but also HNSCC patient-derived tumoroids; (4) Conclusions: The loss of EREG might be considered in clinical settings as a predictive biomarker for patients that might undergo ferroptosis in response to CTX and that might benefit the most from the combination of ferroptosis inducers and CTX. |
| first_indexed | 2024-03-11T07:28:30Z |
| format | Article |
| id | doaj.art-3e9071dc52d54cf3b2ba7636d9de5a6d |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T07:28:30Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-3e9071dc52d54cf3b2ba7636d9de5a6d2023-11-17T07:27:25ZengMDPI AGCells2073-44092023-02-0112573310.3390/cells12050733Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis InductionAude Jehl0Ombline Conrad1Mickaël Burgy2Sophie Foppolo3Romain Vauchelles4Carole Ronzani5Nelly Etienne-Selloum6Marie-Pierre Chenard7Aurélien Danic8Thomas Dourlhes9Claire Thibault10Philippe Schultz11Monique Dontenwill12Sophie Martin13Laboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, FranceLaboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, FranceLaboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, FranceLaboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, FranceLaboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, FranceLaboratory of Design and Application of Bioactive Molecules, University of Strasbourg, UMR7199, CNRS, 67400 Illkirch, FranceLaboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, FranceDepartment of Pathology, Strasbourg University Hospital, 67200 Strasbourg, FranceDepartment of Otolaryngology and Cervico-Facial Surgery, Strasbourg University Hospital, 67200 Strasbourg, FranceDepartment of Otolaryngology and Cervico-Facial Surgery, Strasbourg University Hospital, 67200 Strasbourg, FranceDepartment of Otolaryngology and Cervico-Facial Surgery, Strasbourg University Hospital, 67200 Strasbourg, FranceDepartment of Otolaryngology and Cervico-Facial Surgery, Strasbourg University Hospital, 67200 Strasbourg, FranceLaboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, FranceLaboratory of Bioimaging and Pathology, University of Strasbourg, UMR7021 CNRS, 67401 Illkirch, France(1) Background: Epiregulin (EREG) is a ligand of EGFR and ErB4 involved in the development and the progression of various cancers including head and neck squamous cell carcinoma (HNSCC). Its overexpression in HNSCC is correlated with short overall survival and progression-free survival but predictive of tumors responding to anti-EGFR therapies. Besides tumor cells, macrophages and cancer-associated fibroblasts shed EREG in the tumor microenvironment to support tumor progression and to promote therapy resistance. Although EREG seems to be an interesting therapeutic target, no study has been conducted so far on the consequences of EREG invalidation regarding the behavior and response of HNSCC to anti-EGFR therapies and, more specifically, to cetuximab (CTX); (2) Methods: EREG was silenced in various HNSCC cell lines. The resulting phenotype (growth, clonogenic survival, apoptosis, metabolism, ferroptosis) was assessed in the absence or presence of CTX. The data were confirmed in patient-derived tumoroids; (3) Results: Here, we show that EREG invalidation sensitizes cells to CTX. This is illustrated by the reduction in cell survival, the alteration of cell metabolism associated with mitochondrial dysfunction and the initiation of ferroptosis characterized by lipid peroxidation, iron accumulation and the loss of GPX4. Combining ferroptosis inducers (RSL3 and metformin) with CTX drastically reduces the survival of HNSCC cells but also HNSCC patient-derived tumoroids; (4) Conclusions: The loss of EREG might be considered in clinical settings as a predictive biomarker for patients that might undergo ferroptosis in response to CTX and that might benefit the most from the combination of ferroptosis inducers and CTX.https://www.mdpi.com/2073-4409/12/5/733head and neck cancersEREGferroptosistumoroidbiomarkersmetabolism |
| spellingShingle | Aude Jehl Ombline Conrad Mickaël Burgy Sophie Foppolo Romain Vauchelles Carole Ronzani Nelly Etienne-Selloum Marie-Pierre Chenard Aurélien Danic Thomas Dourlhes Claire Thibault Philippe Schultz Monique Dontenwill Sophie Martin Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction Cells head and neck cancers EREG ferroptosis tumoroid biomarkers metabolism |
| title | Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction |
| title_full | Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction |
| title_fullStr | Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction |
| title_full_unstemmed | Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction |
| title_short | Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction |
| title_sort | blocking ereg gpx4 sensitizes head and neck cancer to cetuximab through ferroptosis induction |
| topic | head and neck cancers EREG ferroptosis tumoroid biomarkers metabolism |
| url | https://www.mdpi.com/2073-4409/12/5/733 |
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