TY  - JOUR
AU  - Zhou, Jiefu
AU  - He, Min
AU  - Zhao, Qiong
AU  - Shi, Enxian
AU  - Wang, Hairong
AU  - Ponkshe, Vaidehi
AU  - Song, Jiahang
AU  - Wu, Zhengquan
AU  - Ji, Dongmei
AU  - Kranz, Gisela
AU  - Tscherne, Anna
AU  - Schwenk-Zieger, Sabina
AU  - Razak, Nilofer Abdul
AU  - Hess, Julia
AU  - Belka, Claus
AU  - Zitzelsberger, Horst
AU  - Ourailidis, Iordanis
AU  - Stögbauer, Fabian
AU  - Boxberg, Melanie
AU  - Budczies, Jan
AU  - Reichel, Christoph A
AU  - Canis, Martin
AU  - Baumeister, Philipp
AU  - Wang, Hongxia
AU  - Unger, Kristian
AU  - Mock, Andreas
AU  - Gires, Olivier
TI  - EGFR-mediated local invasiveness and response to Cetuximab in head and neck cancer.
JO  - Molecular cancer
VL  - 24
IS  - 1
SN  - 1476-4598
CY  - London
PB  - Biomed Central
M1  - DKFZ-2025-00615
SP  - 94
PY  - 2025
AB  - 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.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.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.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.
KW  - Humans
KW  - ErbB Receptors: metabolism
KW  - ErbB Receptors: genetics
KW  - Cetuximab: pharmacology
KW  - Cetuximab: therapeutic use
KW  - Head and Neck Neoplasms: genetics
KW  - Head and Neck Neoplasms: drug therapy
KW  - Head and Neck Neoplasms: pathology
KW  - Head and Neck Neoplasms: metabolism
KW  - Gene Expression Regulation, Neoplastic: drug effects
KW  - Neoplasm Invasiveness
KW  - Cell Line, Tumor
KW  - Gene Regulatory Networks
KW  - Squamous Cell Carcinoma of Head and Neck: genetics
KW  - Squamous Cell Carcinoma of Head and Neck: drug therapy
KW  - Squamous Cell Carcinoma of Head and Neck: pathology
KW  - Squamous Cell Carcinoma of Head and Neck: metabolism
KW  - Animals
KW  - Antineoplastic Agents, Immunological: therapeutic use
KW  - Antineoplastic Agents, Immunological: pharmacology
KW  - Cetuximab (Other)
KW  - EGFR (Other)
KW  - EMT (Other)
KW  - Invasive gene regulatory network (Other)
KW  - Local invasion (Other)
KW  - Oncogene addiction (Other)
KW  - R/M-HNSCC (Other)
KW  - fDEGs (Other)
KW  - ErbB Receptors (NLM Chemicals)
KW  - Cetuximab (NLM Chemicals)
KW  - EGFR protein, human (NLM Chemicals)
KW  - Antineoplastic Agents, Immunological (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40121428
DO  - DOI:10.1186/s12943-025-02290-1
UR  - https://inrepo02.dkfz.de/record/300117
ER  -