Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer
Ziwei Wang,
Tao Wang,
Danni Hong,
Baijun Dong,
Yan Wang,
Huaqiang Huang,
Wenhui Zhang,
Bijun Lian,
Boyao Ji,
Haoqing Shi,
Min Qu,
Xu Gao,
Daofeng Li,
Colin Collins,
Gonghong Wei,
Chuanliang Xu,
Hyung Joo Lee,
Jialiang Huang,
Jing Li
Affiliations
Ziwei Wang
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Tao Wang
Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
Danni Hong
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Baijun Dong
Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Yan Wang
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Huaqiang Huang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China
Wenhui Zhang
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Bijun Lian
Department of Urology, the 903rd PLA Hospital, Hangzhou, Zhejiang 310012, China
Boyao Ji
Department of Histology and Embryology, Naval Medical University, Shanghai 200433, China
Haoqing Shi
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Min Qu
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Xu Gao
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China
Daofeng Li
Department of Genetics, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA
Colin Collins
Department of Urologic Sciences, University of British Columbia, Canada
Gonghong Wei
Fudan University Shanghai Cancer Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China
Chuanliang Xu
Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China; Corresponding author
Hyung Joo Lee
Department of Genetics, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA; Pin Pharmaceuticals, South San Francisco, CA, USA; Corresponding author
Jialiang Huang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China; National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 316005, China; Corresponding author
Jing Li
Department of Bioinformatics, Center for Translational Medicine, Naval Medical University, Shanghai 200433, China; Shanghai Key Laboratory of Cell Engineering, Shanghai, China; Corresponding author
Summary: Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer, with a 10% five-year survival rate. However, little is known about its origin and the mechanisms governing its emergence. Our study characterized ADPC and NEPC in prostate tumors from 7 patients using scRNA-seq. First, we identified two NEPC gene expression signatures representing different phases of trans-differentiation. New marker genes we identified may be used for clinical diagnosis. Second, integrative analyses combining expression and subclonal architecture revealed different paths by which NEPC diverges from the original ADPC, either directly from treatment-naïve tumor cells or from specific intermediate states of treatment-resistance. Third, we inferred a hierarchical transcription factor (TF) network underlying the progression, which involves constitutive regulation by ASCL1, FOXA2, and selective regulation by NKX2-2, POU3F2, and SOX2. Together, these results defined the complex expression profiles and advanced our understanding of the genetic and transcriptomic mechanisms leading to NEPC differentiation.
