Non-melanoma skin cancer, such as squamous cell carcinoma (SCC), is the second most prevalent form of cancer in the Western world; however, the molecular mechanisms causing such tumours are still poorly understood. In their work, Nancy Ling, George Sen and colleagues (Ling et al., 2020) transplant human dermis and primary keratinocytes onto mice to study tumour initiation in the resulting xenograft. Upon co-expression of HRAS with CDK4, the tissue displays progressive epidermal hyperplasia and hyperproliferation, reminiscent of transformation to SCC. Moreover, the protein levels of the cell adhesion proteins CLDN1 and ECAD and the cell polarity regulator PAR3 are reduced after 15 days of HRAS expression. The tumorigenic epidermis also shows a reduced frequency of planar cell divisions. However, this phenotype, and the levels of CLDN1 and ECAD, can be restored by ectopic expression of PAR3. Interestingly, depletion of ECAD five days after HRAS activation equally reduces the frequency of planar cell divisions, suggesting that PAR3 controls cell division planes through ECAD. Finally, the authors demonstrate that inhibition of the MAPK pathway restores PAR3 levels, ECAD and CLDN1 cell junctions and planar cell divisions in the HRAS-expressing xenograft. Thus, this study establishes a model for SCC transformation in primary human keratinocytes with a potential to study pharmacological treatments in vivo and suggests a role for PAR3 in controlling tissue architecture during early SCC development.
PAR3: a novel regulator of tissue architecture during squamous cell carcinoma initiation
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PAR3: a novel regulator of tissue architecture during squamous cell carcinoma initiation. J Cell Sci 1 December 2020; 133 (23): e2303. doi:
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