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

Baijun Dong,Zhongzhong Ji,Jia Wang,Jiahua Pan,Xiaomu Cheng,Wei Xue,Wenqin Luo,Chee Wai Chua,Huadong Lai,Liancheng Fan,Jinming Wang,Man Zhang,Juju Miao,Yinjie Zhu,Wei-Qiang Gao,Helen He Zhu,Yuxiang Fang,Yanqing Wang

doi:10.1038/s42003-020-01476-1

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.

Highlights

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor
Previous genomic analyses have suggested that neuroendocrine prostate cancer (NEPC) are clonally derived from prostate adenocarcinoma (PCA) that usually present luminal-like phenotype[7,12,13], this is the first study to our knowledge that has shown the cellular diversity in human CPRC as well as the cellular phenotypes associated with neuroendocrine differentiation (NED) at singlecell resolution
To unbiasedly evaluate the cellular phenotypes associated with NED, we performed triple IF staining against KRT5, KRT8, and SYP on our large cohort of principal components (PCs) tumor microarrays (TMAs)

Summary

Introduction

Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Current studies support that NEPC tumors arise clonally from prostate adenocarcinoma (PCA)[7], accompanying with a phenotypic transition from acini epithelial tumor cells to NE-like tumor cells[8]. This lineage transition enables tumor cells to evade androgen receptor (AR) pathway inhibitors such as enzalutamide by shedding their dependence on the AR pathway[4,9]. Our results support the epithelial-NE transdifferentiation model regarding the NED in human prostate cancer and offer fresh insights into cellular states and molecular features associated with this process

Methods

Results

Conclusion