The study by Chaffer et al. challenges the traditional hierarchical model of stem cell biology, demonstrating that normal and neoplastic non-stem cells can spontaneously convert to a stem-like state. The researchers identified a subpopulation of basal-like human mammary epithelial cells that can dedifferentiate into stem-like cells, a process that is enhanced by oncogenic transformation. This finding suggests that normal and cancer stem cells can arise de novo from more differentiated cell types, challenging the notion of a unidirectional hierarchy. The study also highlights the importance of the differentiation state of cells-of-origin in determining their behavior post-transformation, with transformed stem-like cells generating more aggressive tumors compared to transformed differentiated cells. These findings have implications for both regenerative medicine and cancer therapy, suggesting that patient-specific adult stem cells may be derived without genetic manipulation and that targeting cancer stem cells alone may not be sufficient to eradicate cancer.The study by Chaffer et al. challenges the traditional hierarchical model of stem cell biology, demonstrating that normal and neoplastic non-stem cells can spontaneously convert to a stem-like state. The researchers identified a subpopulation of basal-like human mammary epithelial cells that can dedifferentiate into stem-like cells, a process that is enhanced by oncogenic transformation. This finding suggests that normal and cancer stem cells can arise de novo from more differentiated cell types, challenging the notion of a unidirectional hierarchy. The study also highlights the importance of the differentiation state of cells-of-origin in determining their behavior post-transformation, with transformed stem-like cells generating more aggressive tumors compared to transformed differentiated cells. These findings have implications for both regenerative medicine and cancer therapy, suggesting that patient-specific adult stem cells may be derived without genetic manipulation and that targeting cancer stem cells alone may not be sufficient to eradicate cancer.