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

doi:10.1016/j.isci.2022.104576

Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer

iScience. 2022 Jun 13;25(7):104576. doi: 10.1016/j.isci.2022.104576. eCollection 2022 Jul 15.

Authors

Ziwei Wang¹, Tao Wang², Danni Hong³, Baijun Dong⁴, Yan Wang¹, Huaqiang Huang³, Wenhui Zhang¹, Bijun Lian⁵, Boyao Ji⁶, Haoqing Shi¹, Min Qu¹, Xu Gao¹, Daofeng Li⁷, Colin Collins⁸, Gonghong Wei⁹, Chuanliang Xu¹, Hyung Joo Lee^{7

10}, Jialiang Huang^{3

11}, Jing Li^{12

13}

Affiliations

¹ Department of Urology, Changhai Hospital, Naval Medical University, Shanghai 200433, China.
² Department of Urology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
³ State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
⁴ Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
⁵ Department of Urology, the 903rd PLA Hospital, Hangzhou, Zhejiang 310012, China.
⁶ Department of Histology and Embryology, Naval Medical University, Shanghai 200433, China.
⁷ Department of Genetics, Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
⁸ Department of Urologic Sciences, University of British Columbia, Canada.
⁹ Fudan University Shanghai Cancer Center, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shanghai Medical College of Fudan University, Shanghai, China.
¹⁰ Pin Pharmaceuticals, South San Francisco, CA, USA.
¹¹ National Institute for Data Science in Health and Medicine, Xiamen University, Xiamen, Fujian 316005, China.
¹² Department of Bioinformatics, Center for Translational Medicine, Naval Medical University, Shanghai 200433, China.
¹³ Shanghai Key Laboratory of Cell Engineering, Shanghai, China.

Abstract

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.

Keywords: Cancer; Cancer systems biology; Transcriptomics.