ALDH-Dependent Glycolytic Activation Mediates Stemness and Paclitaxel Resistance in Patient-Derived Spheroid Models of Uterine Endometrial Cancer

Uterine endometrial cancer is associated with poor survival outcomes in patients with advanced-stage disease. Here, we developed a three-dimensional cell cultivation method of endometrioid cancer stem-like cells with high aldehyde dehydrogenase (ALDH) activity from clinical specimens. ALDH inhibition synergized with paclitaxel to block cancer proliferation. In the clinical setting, high ALDH1A1 expression was associated with poor survival. A high level of ALDH correlated with an increase of glucose uptake, activation of the glycolytic pathway, and elevation of glucose transporter 1 (GLUT1). Blockade of GLUT1 inhibited characteristics of cancer stem cells. Similarly to ALDH inhibition, GLUT1 inhibition synergized with paclitaxel to block endometrial cancer proliferation. Our data indicated that ALDH-dependent GLUT1 activation and the resulting glycolytic activation are of clinical importance for both prognostic evaluation and therapeutic decision-making in endometrial cancer patients. In addition, the synergistic effects of taxane compounds and ALDH or GLUT1 inhibitors may serve as a new clinical treatment option for endometrial cancer. [Display omitted] •Establishment of patient-derived endometrial cancer stem cells with ALDH activity•Endometrial cancer stemness depends on ALDH-mediated glycolysis via GLUT1•High ALDH and GLUT expression is associated with poor outcome in endometrial cancer•Paclitaxel and ALDH or GLUT inhibitor synergistically suppress endometrial cancer In this article, Ishiguro and colleagues demonstrated the stable in vitro cultivation of human endometrial cancer stem cells from clinical specimens. Investigation of patient-derived spheroid cells showed that ALDH-mediated glycolysis through GLUT1 was essential for endometrial cancer stem cells. ALDH and GLUT are novel therapeutic targets in endometrial cancer to complement standard taxane treatment.