Targeting an Autocrine Regulatory Loop in Cancer Stem-like Cells Impairs the Progression and Chemotherapy Resistance of Bladder Cancer

Purpose: Cancer stem-like cells (CSCs) contribute to bladder Cancer chemotherapy resistance and progression, but the associated mechanisms have not been elucidated. This study determined whether blocking an autocrine signaling loop in CSCs improves the therapeutic effects of cis-platinum on bladder Cancer.

Experimental design: The expression of the epithelial marker OV6 and other markers in human bladder Cancer specimens was examined by IHC. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6⁺ and OV6^- bladder Cancer cells were examined. Molecular mechanisms were assessed through RNA-Seq, cytokine antibody arrays, co-immunoprecipitation (co-IP), chromatin immunoprecipitation (ChIP) and other assays. An orthotopic bladder Cancer mouse model was established to evaluate the in vivo effects of a YAP Inhibitor (verteporfin) and a PDGFR Inhibitor (CP-673451) on the cis-platinum resistance of OV6⁺ CSCs in bladder Cancer.

Results: Upregulated OV6 expression positively associated with disease progression and poor prognosis for bladder Cancer patients. Compared with OV6^- cells, OV6⁺ bladder Cancer cells exhibited strong CSC characteristics, including self-renewal, tumor initiation in NOD/SCID mice, and chemotherapy resistance. YAP, which maintains the stemness of OV6⁺ CSCs, triggered PDGFB transcription by recruiting TEAD1. Autocrine PDGF-BB signaling through its receptor PDGFR stabilized YAP and facilitated YAP nuclear translocation. Furthermore, blocking the YAP/TEAD1/PDGF-BB/PDGFR loop with verteporfin or CP-673451 inhibited the cis-platinum resistance of OV6⁺ bladder Cancer CSCs in an orthotopic bladder Cancer model.

Conclusions: OV6 could be a helpful indicator of disease progression and prognosis for patients with bladder Cancer, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced bladder Cancer.