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Tumorigenic transformation of human epithelial cells in vitro has beendescribed experimentally as the potential result of a process known asspontaneous immortalization. In this process a generic series of cell statetransitions occur in which normal epithelial cells acquire a senescent state,later surpassed to attain first a mesenchymal state and then a finalmesenchymal stem-like phenotype, with potential tumorigenic behavior. In thispaper we integrate published data on the molecular components and interactionsthat have been described as key regulators of such cell states and transitions.A large network, that is provided, is constructed and then reduced with the aimof recovering a minimal regulatory core incorporating the necessary andsufficient restrictions to recover the observed cell states and their genericprogression patterns in epithelial-mesenchymal transition. Data is formalizedinto logical regulatory rules that govern the dynamics of each of the network'scomponents as a function of the states of its regulators. The proposed coregene regulatory network attains only three steady-state gene expressionconfigurations that correspond to the profiles characteristic of normalepithelial, senescent, and mesenchymal stem-like cells. Interestingly,epigenetic landscape analyses of the uncovered network shows that it alsorecovers the generic time-ordered transitions documented during tumorigenictransformation in vitro of epithelial cells. The latter strongly correlate withthe patterns observed during the progressive pathological description ofepithelial carcinogenesis in vivo.

Dynamic network and epigenetic landscape model of a regulatory core underlying spontaneous immortalization and epithelial carcinogenesis