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@ARTICLE{Zhou:300117,
      author       = {J. Zhou and M. He and Q. Zhao and E. Shi and H. Wang and V.
                      Ponkshe and J. Song and Z. Wu and D. Ji and G. Kranz and A.
                      Tscherne and S. Schwenk-Zieger and N. A. Razak and J. Hess
                      and C. Belka$^*$ and H. Zitzelsberger and I. Ourailidis and
                      F. Stögbauer and M. Boxberg$^*$ and J. Budczies and C. A.
                      Reichel and M. Canis and P. Baumeister and H. Wang and K.
                      Unger$^*$ and A. Mock and O. Gires},
      title        = {{EGFR}-mediated local invasiveness and response to
                      {C}etuximab in head and neck cancer.},
      journal      = {Molecular cancer},
      volume       = {24},
      number       = {1},
      issn         = {1476-4598},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2025-00615},
      pages        = {94},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Humans / ErbB Receptors: metabolism / ErbB Receptors:
                      genetics / Cetuximab: pharmacology / Cetuximab: therapeutic
                      use / Head and Neck Neoplasms: genetics / Head and Neck
                      Neoplasms: drug therapy / Head and Neck Neoplasms: pathology
                      / Head and Neck Neoplasms: metabolism / Gene Expression
                      Regulation, Neoplastic: drug effects / Neoplasm Invasiveness
                      / Cell Line, Tumor / Gene Regulatory Networks / Squamous
                      Cell Carcinoma of Head and Neck: genetics / Squamous Cell
                      Carcinoma of Head and Neck: drug therapy / Squamous Cell
                      Carcinoma of Head and Neck: pathology / Squamous Cell
                      Carcinoma of Head and Neck: metabolism / Animals /
                      Antineoplastic Agents, Immunological: therapeutic use /
                      Antineoplastic Agents, Immunological: pharmacology /
                      Cetuximab (Other) / EGFR (Other) / EMT (Other) / Invasive
                      gene regulatory network (Other) / Local invasion (Other) /
                      Oncogene addiction (Other) / R/M-HNSCC (Other) / fDEGs
                      (Other) / ErbB Receptors (NLM Chemicals) / Cetuximab (NLM
                      Chemicals) / EGFR protein, human (NLM Chemicals) /
                      Antineoplastic Agents, Immunological (NLM Chemicals)},
      cin          = {MU01},
      ddc          = {570},
      cid          = {I:(DE-He78)MU01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40121428},
      doi          = {10.1186/s12943-025-02290-1},
      url          = {https://inrepo02.dkfz.de/record/300117},
}