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EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer

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...

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Hauptverfasser: Zhou, Jiefu (VerfasserIn) , He, Min (VerfasserIn) , Zhao, Qiong (VerfasserIn) , Shi, Enxian (VerfasserIn) , Wang, Hairong (VerfasserIn) , Ponkshe, Vaidehi (VerfasserIn) , Song, Jiahang (VerfasserIn) , Wu, Zhengquan (VerfasserIn) , Ji, Dongmei (VerfasserIn) , Kranz, Gisela (VerfasserIn) , Tscherne, Anna (VerfasserIn) , Schwenk-Zieger, Sabina (VerfasserIn) , Razak, Nilofer Abdul (VerfasserIn) , Hess, Julia (VerfasserIn) , Belka, Claus (VerfasserIn) , Zitzelsberger, Horst (VerfasserIn) , Ourailidis, Iordanis (VerfasserIn) , Stögbauer, Fabian (VerfasserIn) , Boxberg, Melanie (VerfasserIn) , Budczies, Jan (VerfasserIn) , Reichel, Christoph A. (VerfasserIn) , Canis, Martin (VerfasserIn) , Baumeister, Philipp (VerfasserIn) , Wang, Hongxia (VerfasserIn) , Unger, Kristian (VerfasserIn) , Mock, Andreas (VerfasserIn) , Gires, Olivier (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: 22 March 2025
In: Molecular cancer
Year: 2025, Jahrgang: 24, Pages: 1-26
ISSN:1476-4598
DOI:10.1186/s12943-025-02290-1
Online-Zugang:Verlag, kostenfrei, Volltext: https://doi.org/10.1186/s12943-025-02290-1
Volltext
Verfasserangaben: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 and Olivier Gires
Beschreibung
Zusammenfassung: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.
Beschreibung:Gesehen am 24.02.2026
Beschreibung:Online Resource
ISSN:1476-4598
DOI:10.1186/s12943-025-02290-1

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