Hypoxia-driven hybrid phenotypes in Ewing sarcoma: Insights from computational epithelial-mesenchymal transition modeling

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Author(s):	Silveira, Daner A. ; Gupta, Shantanu ; Brunetto, Andre T. ; Mombach, Jose Carlos Merino ; Sinigaglia, Marialva Total Authors: 5
Document type:	Journal article
Source:	JOURNAL OF COMPUTATIONAL SCIENCE; v. 83, p. 14-pg., 2024-12-01.
Abstract
Ewing sarcoma (ES) is an extremely aggressive pediatric tumor primarily propelled by the EWS::FLI1 fusion protein. This fusion protein plays a pivotal role in various biological processes within ES, including hypoxia and epithelial-mesenchymal transition (EMT). Hypoxia has been documented to trigger EMT, a process that can stabilize a hybrid cell state, enhancing metastatic potential and resistance to drugs. However, the precise mechanisms that sustain this hybrid phenotype during hypoxia in ES have remained enigmatic. Our study introduces a logical model for EMT in ES, underscoring the potential significance of the EWS::FLI1/miR-145 circuit in inducing hybrid states during hypoxia. Furthermore, our findings underscore the necessity for downregulating EWS::FLI1 to fully activate EMT under hypoxic conditions. This model aligns well with results derived from existing literature. These insights underscore the crucial role of EWS::FLI1 in inducing the hybrid state in ES during hypoxia. (AU)

FAPESP's process:	23/14618-8 - Systems biology approach to modeling, analysis, and inference of biological networks
Grantee:	Shantanu Gupta
Support Opportunities:	Scholarships in Brazil - Post-Doctoral