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

Zhou, Jiefu; He, Min; Zhao, Qiong; Shi, Enxian; Wang, Hairong; Ponkshe, Vaidehi; Song, Jiahang; Wu, Zhengquan; Ji, Dongmei; Kranz, Gisela; Tscherne, Anna; Schwenk-Zieger, Sabina; Razak, Nilofer Abdul; Hess, Julia; Belka, Claus; Zitzelsberger, Horst; Ourailidis, Iordanis; Stögbauer, Fabian; Boxberg, Melanie; Budczies, Jan; Reichel, Christoph A.; Canis, Martin; Baumeister, Philipp; Wang, Hongxia; Unger, Kristian; Mock, Andreas; Gires, Olivier (2025): EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer. Molecular Cancer, 24: 94. ISSN 1476-4598

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.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892