Alternative splice variants of DCLK1 mark cancer stem cells, promote self‐renewal and drug‐resistance, and can be targeted to inhibit tumorigenesis in kidney cancer

摘要: Renal cell carcinoma (RCC) is a common and devastating disease characterized by hypoxic microenvironment, epithelial-mesenchymal transition potent resistance to therapy evidencing the presence of cancer stem cells (CSCs). Various CSC markers have been studied in RCC, but overall there limited data on their role most relatively nonspecific. Doublecortin-like kinase 1 (DCLK1) validated marker gastrointestinal tract evidence for an equivalent other cancers accumulating. We used bioinformatics, immunohistochemistry, flow cytometry, spheroid self-renewal chemoresistance assays combination with overexpression siRNA-knockdown study cell-supportive DCLK1 alternative splice variants (DCLK1 ASVs) RCC. To target tumor expressing ASVs directly, we developed novel monoclonal antibody (CBT-15) delivered it systemically RCC xenografts. were overexpressed, enriched together predictive recurrence-free survival patients. In vitro, able directly stimulate essential molecular functional characteristics renal CSCs including expression aldehyde dehydrogenase, FDA-approved receptor tyrosine mTOR inhibitors, while targeted downregulation reversed these characteristics. Finally, targeting ASV-positive CBT-15 blocked tumorigenesis vivo. These findings establish as implications therapy, progression demonstrate therapeutic value DCLK1-targeted antibodies against CSCs.