| Summary: | <i>PTEN</i> is one of the most frequently inactivated tumor suppressor genes in cancer. Loss or variation in <i>PTEN</i> gene/protein levels is commonly observed in a broad spectrum of human cancers, while germline <i>PTEN</i> mutations cause inherited syndromes that lead to increased risk of tumors. <i>PTEN</i> restrains tumorigenesis through different mechanisms ranging from phosphatase-dependent and independent activities, subcellular localization and protein interaction, modulating a broad array of cellular functions including growth, proliferation, survival, DNA repair, and cell motility. The main target of <i>PTEN</i> phosphatase activity is one of the most significant cell growth and pro-survival signaling pathway in cancer: PI3K/AKT/mTOR. Several shreds of evidence shed light on the critical role of <i>PTEN</i> in normal and cancer stem cells (CSCs) homeostasis, with its loss fostering the CSC compartment in both solid and hematologic malignancies. CSCs are responsible for tumor propagation, metastatic spread, resistance to therapy, and relapse. Thus, understanding how alterations of <i>PTEN</i> levels affect CSC hallmarks could be crucial for the development of successful therapeutic approaches. Here, we discuss the most significant findings on <i>PTEN</i>-mediated control of CSC state. We aim to unravel the role of <i>PTEN</i> in the regulation of key mechanisms specific for CSCs, such as self-renewal, quiescence/cell cycle, Epithelial-to-Mesenchymal-Transition (EMT), with a particular focus on <i>PTEN</i>-based therapy resistance mechanisms and their exploitation for novel therapeutic approaches in cancer treatment.
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