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

  • Mol Cancer. 2025 Mar 22;24(1):94. doi: 10.1186/s12943-025-02290-1.
Jiefu Zhou  #  1  2  3  4 ,  Min He  #  1 ,  Qiong Zhao  #  1 ,  Enxian Shi  #  1  5 ,  Hairong Wang  1 ,  Vaidehi Ponkshe  1 ,  Jiahang Song  1 ,  Zhengquan Wu  1 ,  Dongmei Ji  6 ,  Gisela Kranz  1 ,  Anna Tscherne  1 ,  Sabina Schwenk-Zieger  1 ,  Nilofer Abdul Razak  1 ,  Julia Hess  7  8 ,  Claus Belka  8  9  10  11 ,  Horst Zitzelsberger  7 ,  Iordanis Ourailidis  12 ,  Fabian Stögbauer  13 ,  Melanie Boxberg  10 ,  Jan Budczies  9 ,  Christoph A Reichel  1 ,  Martin Canis  1  9 ,  Philipp Baumeister  1  9 ,  Hongxia Wang  6 ,  Kristian Unger  7  8  9  10  11 ,  Andreas Mock  14 ,  Olivier Gires  15
Affiliations
  • 1. Department of Otorhinolaryngology, LMU University Hospital, LMU Munich, Munich, Germany.
  • 2. Department of Sports Medicine, Xiangya Hospital, Central South University, Xiangya Road 87, Changsha, 410008, China.
  • 3. Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Xiangya Road 87, Changsha, 410008, China.
  • 4. Hunan Engineering Research Center of Sports and Health, Changsha, 410008, China.
  • 5. Department of Dermatology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
  • 6. Department of Medical Oncology, Department of Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 7. Research Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München, Deutsches Forschungszentrum Für Gesundheit Und Umwelt (GmbH), Neuherberg, Germany.
  • 8. Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany.
  • 9. Bavarian Cancer Research Center (BZKF), Munich, Germany.
  • 10. German Cancer Consortium (DKTK), Partner Site, Munich, Germany.
  • 11. Comprehensive Cancer Center (CCC), Munich, Germany.
  • 12. Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany.
  • 13. Technical University of Munich, TUM School of Medicine and Health, Institute of General and Surgical Pathology, Munich, Germany.
  • 14. Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
  • 15. Department of Otorhinolaryngology, LMU University Hospital, LMU Munich, Munich, Germany. [email protected].
  • # Contributed equally.
PMID: 40121428 DOI: 10.1186/s12943-025-02290-1
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.

Keywords
Cetuximab; EGFR; EMT; Invasive gene regulatory network; Local invasion; Oncogene addiction; R/M-HNSCC; fDEGs.
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