Abstract
Understanding how disruption of differentiation contributes to the cancer cell phenotype is required to identify alterations essential for malignant transformation and provide experimental basis for their correction. We investigated whether primary quail neuroretina cells, transformed by a conditional v-Src mutant (QNR/v-srcts), could revert to a normal phenotype, in response to the stable expression of constitutively active Notch1 intracellular domain (ICN). This model system was chosen because Notch signaling plays an instructive role in cell fate determination during NR development, and because the intrinsic capacity of QNR cultures to differentiate is blocked by v-Src.We report that stable ICN expression results in suppression of QNR/v-srcts cell transformation in the presence of an active oncoprotein. This phenotypic reversion coincides with a major switch in cell identity, as these undifferentiated cells acquire glial differentiation traits. Both changes appear to be mediated by CBF, a transcription factor that binds to ICN and activates target genes. Cells restored to a normal and differentiated phenotype have undergone changes in the functioning of signaling effectors, essentially regulating cell morphology and cytoskeleton organization. This dominant interference may be partially mediated by an autocrine/paracrine mechanism, as revertant cells secrete a factor(s), which inhibits transformation properties of QNR/v-srcts cells.
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Acknowledgements
We thank Sylvie Gisselbrecht and Christian Larsen for helpful comments on the paper; Jean-Vianney Barnier for providing reagents and advise on PAK1 experiments and Fabrice Cordelières for help with cell imaging. We also thank R Goitsuka, A Sergeant, A Israel, M Castellazzi, S Saule and T Jessell for kindly providing reagents used in this study.This work was supported by the Centre National de Recherche Scientifique, the Institut Curie and the Ligue Nationale Contre le Cancer (Comité Départemental de l'Essonne). SM and SA were supported by fellowships from the Ministère de l'Education Nationale et de la Recherche. SM received further support from the Association pour la Recherche sur le Cancer.
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Mateos, S., Amarir, S., Laugier, D. et al. Stable expression of intracellular Notch suppresses v-Src-induced transformation in avian neural cells. Oncogene 26, 3338–3351 (2007). https://doi.org/10.1038/sj.onc.1210124
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DOI: https://doi.org/10.1038/sj.onc.1210124
