Dados do Trabalho

Título

Investigating Hypoxia-Induced Epithelial-Mesenchymal Transition in Ewing's Sarcoma Cells: A Computational Approach

Introdução

Ewing's Sarcoma (ES) often exhibits hypoxic tumor regions, which may correlate with metastatic dissemination and, consequently, epithelial-mesenchymal transition (EMT). EMT is a biological process facilitating tumor migration, characterized by a phenotypic shift from epithelial to mesenchymal cells. Previous studies across various tumors have indicated the stabilization of a hybrid phenotype during EMT, which displays higher metastatic potential and/or drug resistance than purely epithelial or mesenchymal cells. Nevertheless, the existence and stabilization mechanism of this hybrid phenotype under hypoxia in ES remain elusive.

Objetivo

In this study, we investigated the induction of this phenotype through a proposed computational model, leveraging biochemical insights on ES cells from existing literature.

Método

We translated this data into a network of molecular interactions and modeled the dynamics of node activation and inactivation using logical operators such as AND, OR, and NOT. Model validation was achieved by aligning simulations of node perturbations (either gain or loss of function) with corresponding experimental data reported in the literature.

Resultados

The wild-type simulation of the model revealed 10 stable states, categorized into epithelial (4), hybrid (4), and mesenchymal (2) phenotypes. Consequently, we explored the positive circuits responsible for stabilizing observed hybrid states. Our model suggests that circuits involving molecules such as ZEB2, miR-145, miR-200, miR-129, and TWIST1 may contribute to hybrid state stabilization during EMT. Loss of function of any of these components resulted in the destabilization of the hybrid states in the model.

Conclusão

These findings underscore the significance of these molecules in stabilizing hybrid phenotypes and highlight their potential as targets for therapeutic interventions in ES. Identification of unexplored regulatory mechanisms governing EMT in ES holds promise for the development of novel therapeutic strategies.