ZEB2 at the Crossroads of Development and Cancer Hallmarks: Integrating Experimental Evidence with in silico Analyses

ZEB2 is a pivotal transcriptional controller which lies at the interface between developmental biology and cancer molecular signatures. In addition to its classical role in the epithelial-mesenchymal transition (EMT), ZEB2 controls immune modulation, stemness, angiogenesis, and therapeutic resistance, thus making it the center of tumor progression and clinical outcome. This review is a unique combination of experimental and in silico data to offer a systems-level of understanding of the regulation of ZEB2 by microRNAs, long non-coding RNAs, chromatin remodeling complexes and transcription factor networks. We also integrate bioinformatics-guided inferences between multi-omics data, to obtain new regulatory substructures, prognostic signatures and drug-response associations. With the mapping of the impact of ZEB2 along developmental pathways, metastatic cascades, and the tumor immune microenvironment, we deduce therapeutic exploitable vulnerabilities and biomarker prospects that have been poorly investigated. The synthesis identifies ZEB2 not only as an actor, but as a key modulator of disease phenotypes, a strong translational target for precision medicine and a blueprint towards computational-experimental research synergy.