Epithelial cancers are the most common globally. Despite advancements in treating various forms, few new treatments for disseminated cancers have emerged in the past 15 years. High-resolution single-cell analyses reveal significant intra-tumoral heterogeneity, only partially explained by classical driver mutations, emphasizing tumor cell plasticity and adaptation to the microenvironment. A key driver of this plasticity is EMT, which enables cancer cells to acquire traits like stemness, invasion, and metastasis. EMT is triggered by the microenvironment and maintained by transcription factors such as ZEB1 and ZEB2. While ZEB-mediated EMT’s role in metastasis is well-established, our research shows its expression can induce epithelial dedifferentiation and tumor initiation without additional oncogenic mutations. These insights into plasticity may advance understanding of malignant epithelial tumor progression and contribute to innovative anti-plasticity cancer therapies.