PI3K-PTEN dysregulation leads to mTOR-driven upregulation of the core clock gene BMAL1 in normal and malignant epithelial cells

Adenoid cystic carcinoma (ACC) is an uncommon malignancy of the salivary glands that is characterized by local recurrence and distant metastasis due to its resistance to conventional therapy. Platinum-based therapies have been extensively explored as a treatment for ACC, but they show little effectiveness. Studies have shown that a specific group of tumor cells, harboring characteristics of cancer stem cells (CSCs), are involved in chemoresistance of myeloid leukemias, breast, colorectal and pancreatic carcinomas. Therapeutic strategies that target CSCs improve the survival of patients by decreasing the rates of tumor relapse, and epigenetic drugs, such as histone deacetylase inhibitors (HDACi), have shown promising results in targeting CSCs. In this study, we investigated the effect of the HDACi Suberoylanilide hydroxamic acid (Vorinostat), and cisplatin, alone or in combination, on CSCs and non-CSCs from ACC. We used CSCs as a biological marker for tumor resistance to therapy in patient-derived xenograft (PDX) samples and ACC primary cells. We found that cisplatin reduced tumor viability, but enriched the population of CSCs. Systemic administration of Vorinostat reduced the number of detectable CSCs in vivo and in vitro, and a low dose of Vorinostat decreased tumor cell viability. However, the combination of Vorinostat and cisplatin was extremely effective in depleting CSCs and reducing tumor viability in all ACC primary cells by activating cellular senescence. These observations suggest that HDACi and intercalating agents act more efficiently in combination to destroy tumor cells and their stem cells.

Sensitizing mucoepidermoid carcinomas to chemotherapy by targeted disruption of cancer stem cells

Cancer stem cells (CSCs) are a subpopulation of tumor cells endowed with self-renewal properties and the capacity to dynamically adapt to physiological changes that occur in the tumor microenvironment. CSCs play a central role in resistance to therapy and long-term disease recurrence. Better characterization and understanding of the available in vitro tools to study the biology of CSCs will improve our knowledge of the processes underlying tumor response to therapy, and will help in the screening and development of novel strategies targeting CSCs. We investigated the behavior of different populations of head and neck CSCs grown under ultra-low adhesion conditions. We found that invasion and adhesion differ among tumorsphere subtypes (holospheres, merospheres and paraspheres), and their tumor cell progeny also harbor distinct self-renewal and clonogenic potentials. Furthermore, holospheres contained higher numbers of head and neck CSCs, as detected by the CD44 cancer stem cell marker and aldehyde dehydrogenase (ALDH) enzymatic activity. In addition, holospheres showed reduced proliferation (Ki67), hypoacetylation of histones, and increased expression of the BMI-1 epithelial stem cell marker, suggesting activation of stem cell programs. Collectively, our results suggest that holospheres enrich a specific population of CSCs with enhanced “stemness” and invasive potential.