Single-cell analysis supports a luminal-neuroendocrine transdifferentiation in human prostate cancer

Abstract

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.

Exosomal Long Noncoding RNA HOXD-AS1 Promotes Prostate Cancer Metastasis via miR-361-5p/FOXM1 Axis

“…However, recent studies using more sophisticated models or techniques demonstrated that these two models co-exist and work dependently during the initiation and progression of PCa [42,43]. Pre-existing therapeutic-resistant PCa cells are identi ed with unique gene expression signatures, which could be convertible during PCa progression [43][44][45]. In our present study, we identi ed that CRPC cell secreted exosome could promote the migration of PCa cells in vitro and in vivo by transmitting HOXD-AS1.…”

“…Initially, these two models were proposed to explain the progression of PCa and thought to be mutually exclusive [2,3,[39][40][41]. However, recent studies using more sophisticated models or techniques demonstrated that these two models co-exist and work dependently during the initiation and progression of PCa [42,43]. Pre-existing therapeutic-resistant PCa cells are identi ed with unique gene expression signatures, which could be convertible during PCa progression [43][44][45].…”

MicroRNA-regulated transcriptome analysis identifies four major subtypes with prognostic and therapeutic implications in prostate cancer

“…However, S-IV was also enriched in NEPC signatures, suggesting a possible role of lineage plasticity during S-IV evolution. This was supported by Dong et al who used single-cell RNA sequencing and found that luminal-like adenocarcinoma cells could transdifferentiate into NE cells with loss of luminal markers [42] .…”

Identification of Novel Diagnosis Biomarkers for Therapy-Related Neuroendocrine Prostate Cancer

“…NEPC is a highly aggressive subtype of prostate cancer that is associated with poor survival and developing resistance to novel hormone treatments, including the administration of abiraterone and enzalutamide. Early diagnosis of NEPC and the timely application of treatment for advanced NEPC are difficult to accomplish, however, due to a deficiency of robust molecular biomarkers [ 20 ]. The previously established NEPC score, which was comprehensively analyzed on the basis of DNA alteration, methylation, and RNA expression parameters, has been shown to enable the precise identification of CRPC-NE [ 8 , 9 ].…”