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@ARTICLE{Njouendou:274358,
      author       = {A. J. Njouendou and T. Szarvas and A. A. Z. Tiofack and R.
                      N. Kenfack and P. D. Tonouo and S. N. Ananga and E. H. M. D.
                      Bell and G. Simo and J. D. Hoheisel$^*$ and J. T. Siveke$^*$
                      and S. S. Lueong$^*$},
      title        = {{SOX}2 dosage sustains tumor-promoting inflammation to
                      drive disease aggressiveness by modulating the {FOSL}2/{IL}6
                      axis.},
      journal      = {Molecular cancer},
      volume       = {22},
      number       = {1},
      issn         = {1476-4598},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2023-00560},
      pages        = {52},
      year         = {2023},
      abstract     = {Inflammation is undoubtedly a hallmark of cancer
                      development. Its maintenance within tumors and the
                      consequences on disease aggressiveness are insufficiently
                      understood.Data of 27 tumor entities (about 5000 samples)
                      were downloaded from the TCGA and GEO databases. Multi-omic
                      analyses were performed on these and in-house data to
                      investigate molecular determinants of tumor aggressiveness.
                      Using molecular loss-of-function data, the mechanistic
                      underpinnings of inflammation-induced tumor aggressiveness
                      were addressed. Patient specimens and in vivo disease models
                      were subsequently used to validate findings.There was
                      significant association between somatic copy number
                      alterations (sCNAs) and tumor aggressiveness. SOX2
                      amplification was the most important feature among novel and
                      known aggressiveness-associated alterations.
                      Mechanistically, SOX2 regulates a group of genes, in
                      particular the AP1 transcription factor FOSL2, to sustain
                      pro-inflammatory signaling pathways, such as IL6-JAK-STAT3,
                      TNFA and IL17. FOSL2 was found overexpressed in tumor
                      sections of specifically aggressive cancers. In consequence,
                      prolonged inflammation induces immunosuppression and
                      activates cytidine deamination and thus DNA damage as
                      evidenced by related mutational signatures in aggressive
                      tumors. The DNA damage affects tumor suppressor genes such
                      as TP53, which is the most mutated gene in aggressive tumors
                      compared to less aggressive ones $(38\%$ vs $14\%),$ thereby
                      releasing cell cycle control. These results were confirmed
                      by analyzing tissues from various tumor types and in vivo
                      studies.Our data demonstrate the implication of SOX2 in
                      promoting DNA damage and genome instability by sustaining
                      inflammation via FOSL2/IL6, resulting in tumor
                      aggressiveness.},
      keywords     = {FOSL2 (Other) / Gene expression (Other) / IL6 (Other) /
                      Inflammation (Other) / Mutational signatures (Other) / SOX2
                      (Other) / Somatic copy number alterations (Other) / Tumor
                      aggressiveness (Other)},
      cin          = {B070 / ED01},
      ddc          = {570},
      cid          = {I:(DE-He78)B070-20160331 / I:(DE-He78)ED01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36932385},
      pmc          = {pmc:PMC10022277},
      doi          = {10.1186/s12943-023-01734-w},
      url          = {https://inrepo02.dkfz.de/record/274358},
}