Alonso-Lecue, PilarPedro, Isabel deCoulon, VincentMolinuevo, RutLorz, CorinaSegrelles, CarmenCeballos, LauraLópez-Aventín, DanielGarcía-Valtuille, AnaBernal, José M.Mazorra, FranciscoPujol Vallverdú, Ramon MariaParamio, Jesus M.Sanz, J. RamónFreije, AnaToll Abelló, AgustínGandarillas, Alberto2018-05-032018-05-032017Alonso-Lecue P, de Pedro I, Coulon V, Molinuevo R, Lorz C, Segrelles C. et al. Inefficient differentiation response to cell cycle stress leads to genomic instability and malignant progression of squamous carcinoma cells. Cell Death Dis. 2017 Jun 29;8(6):e2901. DOI: 10.1038/cddis.2017.2592041-4889http://hdl.handle.net/10230/34528Squamous cell carcinoma (SCC) or epidermoid cancer is a frequent and aggressive malignancy. However in apparent paradox it retains the squamous differentiation phenotype except for very dysplastic lesions. We have shown that cell cycle stress in normal epidermal keratinocytes triggers a squamous differentiation response involving irreversible mitosis block and polyploidisation. Here we show that cutaneous SCC cells conserve a partial squamous DNA damage-induced differentiation response that allows them to overcome the cell division block. The capacity to divide in spite of drug-induced mitotic stress and DNA damage made well-differentiated SCC cells more genomically instable and more malignant in vivo. Consistently, in a series of human biopsies, non-metastatic SCCs displayed a higher degree of chromosomal alterations and higher expression of the S phase regulator Cyclin E and the DNA damage signal γH2AX than the less aggressive, non-squamous, basal cell carcinomas. However, metastatic SCCs lost the γH2AX signal and Cyclin E, or accumulated cytoplasmic Cyclin E. Conversely, inhibition of endogenous Cyclin E in well-differentiated SCC cells interfered with the squamous phenotype. The results suggest a dual role of cell cycle stress-induced differentiation in squamous cancer: the resulting mitotic blocks would impose, when irreversible, a proliferative barrier, when reversible, a source of genomic instability, thus contributing to malignancy.application/pdfengCopyright © 2017 The Author(s). Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/CarcinomaCarcinogènesiPell -- Càncerinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/cddis.2017.259info:eu-repo/semantics/openAccess