ARTICLE ABSTRACT
Prostate cancer (PCa) is the second leading cause of non-cutaneous cancer-related deaths in American men. Androgen deprivation therapy (ADT), radical prostatectomy, and radiation therapy remain the primary treatment for early-stage PCa patients (castration-sensitive: CSPC). Following ADT, many patients ultimately develop metastatic castration-resistant PCa (mCRPC). Standard chemotherapy options for CRPC are Docetaxel (DTX) and Cabazitaxel (CBZ), which increase median survival, although the development of resistance is common. Cancer-stem-like cells possess mesenchymal phenotypes (EMT) and play crucial roles in tumor initiation and progression of mCRPC. We have shown that low-dose continuous administration of topotecan (METRO-TOPO) inhibits PCa growth by interfering with key cancer-pathway genes. This study utilized bulk and single-cell or whole-transcriptome analysis (RNA-sequencing and scRNAseq), and we observed greater expression of several EMT markers, including VIM, HAS3, S100A6, TGFB1, CD44, CD55, and CD109 in European American and African American aggressive variant PCa (AVPC) subtypes - mCRPC, neuroendocrine variant (NEPC), and taxane-resistant. The taxane-resistant gene FSCN1 was also expressed highly in single-cell sub-clonal populations in mCRPC. Further, metronomic-topotecan single-agent and combinations with DTX downregulated these EMT markers as well as CD44+ and CD44+/CD133+ “stem-like” cell populations. A microfluidic chip-based cell invasion assay revealed that METRO-TOPO treatment as a single-agent or in combination with DTX was potentially effective against invasive PCa spread. Our RNAseq and scRNAseq analysis were supported by in silico and in vitro studies, suggesting METRO-TOPO combined with DTX may inhibit oncogenic progression by reducing cancer stemness in AVPC through the inhibition of EMT markers and multiple oncogenic factors/pathways.
