EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer
Abstract Background Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is a severe, frequently lethal condition. Oncogene addiction to epidermal growth factor receptor (EGFR) is a hallmark of HNSCC, but the clinical efficacy of EGFR-targeted therapies remains low. Understanding m...
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2025-03-01
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| Series: | Molecular Cancer |
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| Online Access: | https://doi.org/10.1186/s12943-025-02290-1 |
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| author | Jiefu Zhou Min He Qiong Zhao Enxian Shi Hairong Wang Vaidehi Ponkshe Jiahang Song Zhengquan Wu Dongmei Ji Gisela Kranz Anna Tscherne Sabina Schwenk-Zieger Nilofer Abdul Razak Julia Hess Claus Belka Horst Zitzelsberger Iordanis Ourailidis Fabian Stögbauer Melanie Boxberg Jan Budczies Christoph A. Reichel Martin Canis Philipp Baumeister Hongxia Wang Kristian Unger Andreas Mock Olivier Gires |
| author_facet | Jiefu Zhou Min He Qiong Zhao Enxian Shi Hairong Wang Vaidehi Ponkshe Jiahang Song Zhengquan Wu Dongmei Ji Gisela Kranz Anna Tscherne Sabina Schwenk-Zieger Nilofer Abdul Razak Julia Hess Claus Belka Horst Zitzelsberger Iordanis Ourailidis Fabian Stögbauer Melanie Boxberg Jan Budczies Christoph A. Reichel Martin Canis Philipp Baumeister Hongxia Wang Kristian Unger Andreas Mock Olivier Gires |
| author_sort | Jiefu Zhou |
| collection | DOAJ |
| description | Abstract Background Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is a severe, frequently lethal condition. Oncogene addiction to epidermal growth factor receptor (EGFR) is a hallmark of HNSCC, but the clinical efficacy of EGFR-targeted therapies remains low. Understanding molecular networks governing EGFR-driven progression is paramount to the exploration of (co)-treatment targets and predictive markers. Methods We performed function-based mapping of differentially expressed genes in EGFR-mediated local invasion (fDEGs) using photoconvertible tracers and RNA-sequencing (RNA-seq) in a cellular 3D-model. Results Upon alignment with public single-cell RNA-seq (scRNA-seq) datasets and HNSCC-specific regulons, a gene regulatory network of local invasion (invGRN) was inferred from gene expression data, which was overrepresented in budding tumors. InvGRN comprises the central hubs inhibin subunit beta alpha (INHBA) and snail family transcriptional repressor 2 (SNAI2), and druggable fDEGs integrin subunit beta 4 (ITGB4), laminin 5 (LAMB3/LAMC2), and sphingosine kinase 1 (SPHK1). Blockade of INHBA repressed local invasion and was reverted by activin A, laminin 5, and sphingosine-1-phosphate, demonstrating a functional interconnectivity of the invGRN. Epithelial-to-mesenchymal transition (EMT) of malignant cells and the invGRN are induced by newly defined EGFR-activity subtypes with prognostic value that are promoted by amphiregulin (AREG) and epiregulin (EREG). Importantly, co-inhibition of SPHK1 showed synthetic effects on Cetuximab-mediated invasion blockade and high expression of selected fDEGs was associated with response to Cetuximab in patient-derived xenotransplantation (PDX) and R/M-HNSCC patients. Conclusions We describe an actionable network of EGFR-mediated local invasion and define druggable effectors with predictive potential regarding the response of R/M-HNSCC to Cetuximab. |
| format | Article |
| id | doaj-art-2a602574c46446daaec6fe46c9bfe846 |
| institution | Kabale University |
| issn | 1476-4598 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj-art-2a602574c46446daaec6fe46c9bfe8462025-08-20T03:41:39ZengBMCMolecular Cancer1476-45982025-03-0124112610.1186/s12943-025-02290-1EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancerJiefu Zhou0Min He1Qiong Zhao2Enxian Shi3Hairong Wang4Vaidehi Ponkshe5Jiahang Song6Zhengquan Wu7Dongmei Ji8Gisela Kranz9Anna Tscherne10Sabina Schwenk-Zieger11Nilofer Abdul Razak12Julia Hess13Claus Belka14Horst Zitzelsberger15Iordanis Ourailidis16Fabian Stögbauer17Melanie Boxberg18Jan Budczies19Christoph A. Reichel20Martin Canis21Philipp Baumeister22Hongxia Wang23Kristian Unger24Andreas Mock25Olivier Gires26Department of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Medical Oncology, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan UniversityDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichResearch Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München, Deutsches Forschungszentrum Für Gesundheit Und Umwelt (GmbH)Department of Radiation Oncology, University Hospital, LMU MunichResearch Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München, Deutsches Forschungszentrum Für Gesundheit Und Umwelt (GmbH)Institute of Pathology, University of HeidelbergTechnical University of Munich, TUM School of Medicine and Health, Institute of General and Surgical PathologyGerman Cancer Consortium (DKTK)Bavarian Cancer Research Center (BZKF)Department of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichDepartment of Medical Oncology, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan UniversityResearch Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München, Deutsches Forschungszentrum Für Gesundheit Und Umwelt (GmbH)Institute of Pathology, Faculty of Medicine, LMU MunichDepartment of Otorhinolaryngology, LMU University Hospital, LMU MunichAbstract Background Recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC) is a severe, frequently lethal condition. Oncogene addiction to epidermal growth factor receptor (EGFR) is a hallmark of HNSCC, but the clinical efficacy of EGFR-targeted therapies remains low. Understanding molecular networks governing EGFR-driven progression is paramount to the exploration of (co)-treatment targets and predictive markers. Methods We performed function-based mapping of differentially expressed genes in EGFR-mediated local invasion (fDEGs) using photoconvertible tracers and RNA-sequencing (RNA-seq) in a cellular 3D-model. Results Upon alignment with public single-cell RNA-seq (scRNA-seq) datasets and HNSCC-specific regulons, a gene regulatory network of local invasion (invGRN) was inferred from gene expression data, which was overrepresented in budding tumors. InvGRN comprises the central hubs inhibin subunit beta alpha (INHBA) and snail family transcriptional repressor 2 (SNAI2), and druggable fDEGs integrin subunit beta 4 (ITGB4), laminin 5 (LAMB3/LAMC2), and sphingosine kinase 1 (SPHK1). Blockade of INHBA repressed local invasion and was reverted by activin A, laminin 5, and sphingosine-1-phosphate, demonstrating a functional interconnectivity of the invGRN. Epithelial-to-mesenchymal transition (EMT) of malignant cells and the invGRN are induced by newly defined EGFR-activity subtypes with prognostic value that are promoted by amphiregulin (AREG) and epiregulin (EREG). Importantly, co-inhibition of SPHK1 showed synthetic effects on Cetuximab-mediated invasion blockade and high expression of selected fDEGs was associated with response to Cetuximab in patient-derived xenotransplantation (PDX) and R/M-HNSCC patients. Conclusions We describe an actionable network of EGFR-mediated local invasion and define druggable effectors with predictive potential regarding the response of R/M-HNSCC to Cetuximab.https://doi.org/10.1186/s12943-025-02290-1Oncogene addictionEGFRR/M-HNSCCCetuximabEMTLocal invasion |
| spellingShingle | Jiefu Zhou Min He Qiong Zhao Enxian Shi Hairong Wang Vaidehi Ponkshe Jiahang Song Zhengquan Wu Dongmei Ji Gisela Kranz Anna Tscherne Sabina Schwenk-Zieger Nilofer Abdul Razak Julia Hess Claus Belka Horst Zitzelsberger Iordanis Ourailidis Fabian Stögbauer Melanie Boxberg Jan Budczies Christoph A. Reichel Martin Canis Philipp Baumeister Hongxia Wang Kristian Unger Andreas Mock Olivier Gires EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer Molecular Cancer Oncogene addiction EGFR R/M-HNSCC Cetuximab EMT Local invasion |
| title | EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer |
| title_full | EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer |
| title_fullStr | EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer |
| title_full_unstemmed | EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer |
| title_short | EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer |
| title_sort | egfr mediated local invasiveness and response to cetuximab in head and neck cancer |
| topic | Oncogene addiction EGFR R/M-HNSCC Cetuximab EMT Local invasion |
| url | https://doi.org/10.1186/s12943-025-02290-1 |
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