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 (BCa) 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 BCa. Experimental Design: The expression of the epithelial marker OV6 and other markers in human BCa specimens was examined by immunohistochemistry. The CSC properties of magnetic-activated cell sorting (MACS)-isolated OV6+ and OV6- BCa 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 BCa 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 BCa. Results: Up-regulated OV6 expression positively associated with disease progression and poor prognosis for BCa patients. Compared with OV6- cells, OV6+ BCa 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+ BCa CSCs in an orthotopic BCa model. Conclusions: OV6 could be a helpful indicator of disease progression and prognosis for BCa patients, and targeting the autocrine YAP/TEAD1/PDGF-BB/PDGFR loop might serve as a remedy for cis-platinum resistance in patients with advanced BCa.

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