Synthesis of EMT signalling in cSCC based on clinical and experimental studies evaluated in this review (Supplementary Table 1 and 2). The signalling investigated by cell line-based studies was merged in this EMT pathway map under the assumption of transferability between the different aetiologies and models. Multiple changes can induce EMT in cSCC. Hormonal, cytokine, growth factor, ECM signalling all contribute cooperatively to the extent and nature of the EMT programme. Central signalling hubs such as Akt, MKKs or NFκB are attractive drug targets that could be used to attenuate EMT in cSCC [76]

Synthesis of EMT signalling in cSCC based on clinical and experimental studies evaluated in this review (Supplementary Table 1 and 2). The signalling investigated by cell line-based studies was merged in this EMT pathway map under the assumption of transferability between the different aetiologies and models. Multiple changes can induce EMT in cSCC. Hormonal, cytokine, growth factor, ECM signalling all contribute cooperatively to the extent and nature of the EMT programme. Central signalling hubs such as Akt, MKKs or NFκB are attractive drug targets that could be used to attenuate EMT in cSCC [76]

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Cutaneous squamous cell carcinoma (cSCC) is a disease with globally rising incidence and poor prognosis for patients with advanced or metastatic disease. Epithelial-mesenchymal transition (EMT) is a driver of metastasis in many carcinomas, and cSCC is no exception. We aimed to provide a systematic overview of the clinical and experimental evidence...

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... synergistically with dysregulated Wnt/β-catenin signalling, an inducer of cancer stem cell properties [100][101][102]. Clinical evidence shows the co-localization of βcatenin and E-cadherin at cellular junctions [51,69]. Loss of E-cadherin is associated with the disassembly of those junctions, decreased adherence and increased nuclear β-catenin ( Fig. 2 and 4) [51,69]. The transcriptional repression of E-cadherin is mediated by canonical EMT-TFs (e.g. Snail) as well as other transcription factors such as Grhl3 (Fig. 4) [61,103]. Increased nuclear β-catenin has been observed in tumors with poor differentiation and correlated to lymph node metastasis ...
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... and E-cadherin at cellular junctions [51,69]. Loss of E-cadherin is associated with the disassembly of those junctions, decreased adherence and increased nuclear β-catenin ( Fig. 2 and 4) [51,69]. The transcriptional repression of E-cadherin is mediated by canonical EMT-TFs (e.g. Snail) as well as other transcription factors such as Grhl3 (Fig. 4) [61,103]. Increased nuclear β-catenin has been observed in tumors with poor differentiation and correlated to lymph node metastasis ...
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... efforts, some drugs have elicited the desired reversion of an EMT phenotype in cSCC cell lines and xenografts (Table 2). Successful induction of MET was mostly achieved by targeting four major signalling pathways responsible for the induction EMT in cSCC: EGFR signalling, the PI3K/Akt/mTOR pathway, TGF-β signalling and NFκB signalling (refer to Fig. 4 for details). The kinase, Akt, takes a central role here with several drugs, reducing its activity also favourably modulating EMT marker expression, reducing migratory and invasive properties. Direct pharmaceutical inhibition of Akt successfully induced apoptosis, reduced tumor growth in xenografts whilst inducing MET [110,145]. ...
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... the increased activation of Akt, overexpression of EGFR and the presence of active nuclear IκKβ as predictors of aggressive and metastatic disease [56,160,161]. Confirming these findings, in vitro studies identify the canonical EGFR/MAPK-pathway, the PI3K/Akt-pathway, and the NFκB-pathway as the central pillars of EMT regulation in cSCC (Fig. 4). Akt can be activated via PI3K and PDK1 by mitogen receptors such as EGFR [162]. Another important hub, GSK3-β, connects Akt signalling with NFκB signalling as well as stemness signalling through stabilization of β-catenin [163,164]. The fourth pillar of EMT (Fig. 4), canonical TGF-β signalling, was described in an early study by ...
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... and the NFκB-pathway as the central pillars of EMT regulation in cSCC (Fig. 4). Akt can be activated via PI3K and PDK1 by mitogen receptors such as EGFR [162]. Another important hub, GSK3-β, connects Akt signalling with NFκB signalling as well as stemness signalling through stabilization of β-catenin [163,164]. The fourth pillar of EMT (Fig. 4), canonical TGF-β signalling, was described in an early study by Davies et al. [150]. The minimal requirement of the immortal keratinocyte cell line, HaCaT, to undergo EMT is a combination treatment of EGF and TGF-β. The activation of EGFR signalling can be mimicked by transfection with mutant Ras. Constitutively active Ras was able to ...
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... during cSCC pathogenesis [64,66]. TGF-β and underlying SMAD, ERK and P38 signalling induces the transcription of multiple EMT related proteins such as COX-2, Snail, Slug, proteases (MMP-2, MMP-9) and SERPINE1 [47,156,165]. An overview over the complex signalling circuity underlying EMT and the crosstalk between the four pillars is provided in Fig. ...
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... Consequently, reducing EMT and associated stemness might prove useful in assisting current and future therapeutics to overcome these challenges. As shown in Table 2, targeting canonical EGFR, canonical TGF-βR, NFκB, and PI3K-signalling successfully reverse EMT. Within in these pathways, connecting hubs such as AKT pose interesting drug targets (Fig. 4). Downstream effector kinases such as ERK or p38 can also be used to attenuate EMT and prevent the transcriptional induction of EMT-TFs. However, the targeted treatments used in the past are merely valuable proof-of-concept studies due to their insufficient drug properties for clinical translation. Lacking selectivity, unclear mechanism ...