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@ARTICLE{Horny:275483,
      author       = {K. Horny$^*$ and C. Sproll and L. Peiffer$^*$ and F.
                      Furtmann$^*$ and P. Gerhardt$^*$ and J. Gravemeyer$^*$ and
                      N. H. Stoecklein and I. Spassova-Gießler$^*$ and J.
                      Becker$^*$},
      title        = {{M}esenchymal-epithelial transition in lymph node
                      metastases of oral squamous cell carcinoma is accompanied by
                      {ZEB}1 expression.},
      journal      = {Journal of translational medicine},
      volume       = {21},
      number       = {1},
      issn         = {1479-5876},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DKFZ-2023-00790},
      pages        = {267},
      year         = {2023},
      abstract     = {Oral squamous cell carcinoma (OSCC), an HPV-negative head
                      and neck cancer, frequently metastasizes to the regional
                      lymph nodes but only occasionally beyond. Initial phases of
                      metastasis are associated with an epithelial-mesenchymal
                      transition (EMT), while the consolidation phase is
                      associated with mesenchymal-epithelial transition (MET).
                      This dynamic is referred to as epithelial-mesenchymal
                      plasticity (EMP). While it is known that EMP is essential
                      for cancer cell invasion and metastatic spread, less is
                      known about the heterogeneity of EMP states and even less
                      about the heterogeneity between primary and metastatic
                      lesions.To assess both the heterogeneity of EMP states in
                      OSCC cells and their effects on stromal cells, we performed
                      single-cell RNA sequencing (scRNAseq) of 5 primary tumors, 9
                      matching metastatic and 5 tumor-free lymph nodes and
                      re-analyzed publicly available scRNAseq data of 9 additional
                      primary tumors. For examining the cell type composition, we
                      performed bulk transcriptome sequencing. Protein expression
                      of selected genes were confirmed by
                      immunohistochemistry.From the 23 OSCC lesions, the single
                      cell transcriptomes of a total of 7263 carcinoma cells were
                      available for in-depth analyses. We initially focused on one
                      lesion to avoid confounding inter-patient heterogeneity and
                      identified OSCC cells expressing genes characteristic of
                      different epithelial and partial EMT stages. RNA velocity
                      and the increase in inferred copy number variations
                      indicated a progressive trajectory towards epithelial
                      differentiation in this metastatic lesion, i.e., cells
                      likely underwent MET. Extension to all samples revealed a
                      less stringent but essentially similar pattern.
                      Interestingly, MET cells show increased activity of the
                      EMT-activator ZEB1. Immunohistochemistry confirmed that ZEB1
                      was co-expressed with the epithelial marker cornifin B in
                      individual tumor cells. The lack of E-cadherin mRNA
                      expression suggests this is a partial MET. Within the tumor
                      microenvironment we found immunomodulating fibroblasts that
                      were maintained in primary and metastatic OSCC.This study
                      reveals that EMP enables different partial EMT and
                      epithelial phenotypes of OSCC cells, which are endowed with
                      capabilities essential for the different stages of the
                      metastatic process, including maintenance of cellular
                      integrity. During MET, ZEB1 appears to be functionally
                      active, indicating a more complex role of ZEB1 than mere
                      induction of EMT.},
      keywords     = {EMT (Other) / Epithelial–mesenchymal plasticity (Other) /
                      Heterogeneity (Other) / MET (Other) / Oral cavity (Other) /
                      Partial EMT (Other) / Single cell RNA (Other) / Squamous
                      cell carcinoma (Other) / ZEB1 (Other)},
      cin          = {ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)ED01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37076857},
      doi          = {10.1186/s12967-023-04102-w},
      url          = {https://inrepo02.dkfz.de/record/275483},
}