  Tumorigenic transformation of human epithelial cells in vitro has been
described experimentally as the potential result of a process known as
spontaneous immortalization. In this process a generic series of cell state
transitions occur in which normal epithelial cells acquire a senescent state,
later surpassed to attain first a mesenchymal state and then a final
mesenchymal stem-like phenotype, with potential tumorigenic behavior. In this
paper we integrate published data on the molecular components and interactions
that 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 aim
of recovering a minimal regulatory core incorporating the necessary and
sufficient restrictions to recover the observed cell states and their generic
progression patterns in epithelial-mesenchymal transition. Data is formalized
into logical regulatory rules that govern the dynamics of each of the network's
components as a function of the states of its regulators. The proposed core
gene regulatory network attains only three steady-state gene expression
configurations that correspond to the profiles characteristic of normal
epithelial, senescent, and mesenchymal stem-like cells. Interestingly,
epigenetic landscape analyses of the uncovered network shows that it also
recovers the generic time-ordered transitions documented during tumorigenic
transformation in vitro of epithelial cells. The latter strongly correlate with
the patterns observed during the progressive pathological description of
epithelial carcinogenesis in vivo.
