xav939 and Kidney-Neoplasms

Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Carcinoma, Renal Cell; Cell Line, Tumor; Cell Proliferation; Female; Heterocyclic Compounds, 3-Ring; Humans; Kidney; Kidney Neoplasms; Male; Mice; Middle Aged; Neoplastic Stem Cells; Primary Cell Culture; Pyrimidinones; Receptors, Notch; RNA, Small Interfering; Signal Transduction; Single-Cell Analysis; Spheroids, Cellular; Wnt Proteins; Xenograft Model Antitumor Assays