Abstract
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.
Highlights
Current treatments for clear cell renal cell cancer are insufficient because two-thirds of patients with metastases progress within two years
While the cancer stem cell genes and WNT and NOTCH signaling genes were not included in this list, we found that clusters 1 and 3 showed higher expression of WNT and NOTCH pathway genes, stem cell genes and kidney-specific genes, for instance LGR4, TCF7L2, JAG1, ALDH1A1, and PAX2 (Fig. 5c)
We examined sphere cultures using other inhibitors directed against the receptors used above for sorting cancer stem cell (CSC), but these were less effective than WNT and NOTCH inhibition: the MET inhibitor Crizotinib[47] inhibited sphere growth in 44% of specimens, and the CXCR4 chemokine receptor inhibitor AMD310048 in 17%
Summary
Current treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. 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. Organoids derived from kidney tumors have only recently been described; here we report a well-characterized organoid model from human primary ccRCCs. In addition, patient-derived xenografts (PDXs) derived through transplantations of cells and disease tissues into immune-compromised mice have been used as models to study renal carcinogenesis[13,14]. The fidelity that is maintained through re-passaging makes it possible to produce animals whose tumors replicate that of an individual patient and can be used to search for effective treatments
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