title: Gene regulatory network underlying the immortalization of epithelial cells.
abstract: Tumorigenic transformation of human epithelial cells in vitro has been described experimentally as the potential result of spontaneous immortalization. This process is characterized by a series of cell-state transitions, in which normal epithelial cells acquire first a senescent state which is later surpassed to attain a mesenchymal stem-like phenotype with a potentially tumorigenic behavior. In this paper we aim to provide a system-level mechanistic explanation to the emergence of these cell types, and to the time-ordered transition patterns that are common to neoplasias of epithelial origin. To this end, we first integrate published functional and well-curated molecular data of the components and interactions that have been found to be involved in such cell states and transitions into a network of 41 molecular components. We then reduce this initial network by removing simple mediators (i.e., linear pathways), and formalize the resulting regulatory core into logical rules that govern the dynamics of each of the network components as a function of the states of its regulators.
  
  
  
  Computational dynamic analysis shows that our proposed Gene Regulatory Network model recovers exactly three attractors, each of them defined by a specific gene expression profile that corresponds to the epithelial, senescent, and mesenchymal stem-like cellular phenotypes, respectively. We show that although a mesenchymal stem-like state can be attained even under unperturbed physiological conditions, the likelihood of converging to this state is increased when pro-inflammatory conditions are simulated, providing a systems-level mechanistic explanation for the carcinogenic role of chronic inflammatory conditions observed in the clinic. We also found that the regulatory core yields an epigenetic landscape that restricts temporal patterns of progression between the steady states, such that recovered patterns resemble the time-ordered transitions observed during the spontaneous immortalization of epithelial cells, both in vivo and in vitro.
  
  
  
  Our study strongly suggests that the in vitro tumorigenic transformation of epithelial cells, which strongly correlates with the patterns observed during the pathological progression of epithelial carcinogenesis in vivo, emerges from underlying regulatory networks involved in epithelial trans-differentiation during development.
authors.affiliation: Centro de Investigación y Desarrollo en Ciencias de la Salud (CIDICS), Universidad Autonoma de Nuevo Leon, A. P. 14-740, México, 07300, D.F, México.
authors.forename: Luis Fernando
authors.initials: LF
authors.lastname: Méndez-López
authors.affiliation: Centro de Ciencias de la Complejidad, UNAM, Cd. Universitaria, México, 04510, D.F, México.
authors.forename: Jose
authors.initials: J
authors.lastname: Davila-Velderrain
authors.affiliation: Instituto de Ecología, UNAM, Cd. Universitaria, México, 04510, D.F, México.|Centro de Ciencias de la Complejidad, UNAM, Cd. Universitaria, México, 04510, D.F, México.
authors.forename: Elisa
authors.initials: E
authors.lastname: Domínguez-Hüttinger
authors.affiliation: Departamento de Control Automático, Cinvestav-IPN, A. P. 14-740, México, 07300, D.F, México.
authors.forename: Christian
authors.initials: C
authors.lastname: Enríquez-Olguín
authors.affiliation: Departamento de Control Automático, Cinvestav-IPN, A. P. 14-740, México, 07300, D.F, México. juancarlos_martinez-garcia@conciliencia.org.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Martínez-García
authors.affiliation: Instituto de Ecología, UNAM, Cd. Universitaria, México, 04510, D.F, México. eabuylla@gmail.com.|Centro de Ciencias de la Complejidad, UNAM, Cd. Universitaria, México, 04510, D.F, México. eabuylla@gmail.com.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Alvarez-Buylla
mesh_terms: D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D053263:Gene Regulatory Networks; D059630:Mesenchymal Stem Cells / Q000166:cytology; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype
keywords: Boolean models; Carcinomas; Epigenetic landscape; Gene regulatory networks; Phenotypic attractors