Cellular Pliancy and the Multistep Process of Tumorigenesis Alain Puisieux, Roxane M. Pommier, Anne-Pierre Morel, Fabrice Lavial  Cancer Cell  Volume 33, Issue 2, Pages 164-172 (February 2018) DOI: 10.1016/j.ccell.2018.01.007 Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 1 General Features of Pediatric Cancers of Developmental Origin and Adult Carcinomas Retinoblastomas, atypical teratoid/rhabdoid tumors (AT/RTs), and MYCN-amplified neuroblastomas (MNA-neuroblastoma) are shown to illustrate pediatric cancers, while basal-like breast cancers and pancreatic cancers are shown as representative examples of adult carcinomas. Activation of oncogenes (by mutation or amplification) is indicated in red, and inactivation of tumor suppressor genes (by mutation and/or deletion) is indicated in green. Cancer Cell 2018 33, 164-172DOI: (10.1016/j.ccell.2018.01.007) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 2 p53, a Guardian of Tissue and Cell Identity and a Sensor of Cellular Stress During embryogenesis, p53 acts as a master regulator of cell cooperation. Moreover, p53 constrains the cellular plasticity of epithelial cells by activating the expression of miR-200, miR-34, and miR-192 family members, by repressing pluripotent factors, such as NANOG and OCT4, and by maintaining DNA methylation homeostasis. In differentiated cells, p53 acts as a guardian of genomic integrity by controlling the G1-S cell-cycle checkpoint and by activating fail-safe programs in response to cancer-associated DNA damage and stress signals. MET, mesenchymal-to-epithelial transition. Cancer Cell 2018 33, 164-172DOI: (10.1016/j.ccell.2018.01.007) Copyright © 2018 Elsevier Inc. Terms and Conditions

Figure 3 Landscape of Pediatric and Adult Cancer Development An adaption of the Waddington landscape to schematize the impact of cellular differentiation on the roads toward malignancy. On the left-hand side of the figure, normal embryonic cells are shown in the upper part, and normal adult counterparts are positioned under the black dotted line. During differentiation, cells are guided toward well-defined cell fates, with the stabilization of cell states highlighted by the deepening of the valleys (Feinberg et al., 2016; Waddington, 1957). On the right-hand side, each arrow indicates a process of malignant transformation and tumorigenesis, and each star represents a genetic or epigenetic driver event. As depicted by the top arrow, embryonic cells at a particular developmental stage exhibit a high propensity to malignant transformation when sustaining a specific oncogene activation, limiting the number of events required to reach malignancy. As a consequence, corresponding tumors usually develop with a short delay and exhibit a low frequency of TP53 mutation and low genomic instability. In contrast, malignant transformation of adult differentiated cells, represented by the bottom arrow, frequently involves an early dedifferentiation step, allowing cells to “climb the hill” and regain pliancy for malignant transformation. In that context, a high number of genetic and epigenetic hits (including TP53 mutation) is required to trigger the acquisition of malignant properties, a process fostered by the emergence of genomic instability. Finally, tumors arising from the transformation of adult undifferentiated cells may share general features with pediatric cancers of developmental origin, due to the high intrinsic pliancy of the cell of origin. Cancer Cell 2018 33, 164-172DOI: (10.1016/j.ccell.2018.01.007) Copyright © 2018 Elsevier Inc. Terms and Conditions