TY - JOUR
T1 - Single-cell transcriptional regulation and genetic evolution of neuroendocrine prostate cancer
AU - Wang, Ziwei
AU - Wang, Tao
AU - Hong, Danni
AU - Dong, Baijun
AU - Wang, Yan
AU - Huang, Huaqiang
AU - Zhang, Wenhui
AU - Lian, Bijun
AU - Ji, Boyao
AU - Shi, Haoqing
AU - Qu, Min
AU - Gao, Xu
AU - Li, Daofeng
AU - Collins, Colin
AU - Wei, Gonghong
AU - Xu, Chuanliang
AU - Lee, Hyung Joo
AU - Huang, Jialiang
AU - Li, Jing
N1 - Funding Information:
National Natural Science Foundation of China grant 31871317 (J.H).
Funding Information:
National Natural Science Foundation of China grant 32070635 (J.H).
Funding Information:
National Natural Science Foundation of China grant 82022055 (J.L).
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/7/15
Y1 - 2022/7/15
N2 - 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.
AB - 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.
KW - Cancer
KW - Cancer systems biology
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85132926506&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2022.104576
DO - 10.1016/j.isci.2022.104576
M3 - Article
C2 - 35789834
AN - SCOPUS:85132926506
SN - 2589-0042
VL - 25
JO - iScience
JF - iScience
IS - 7
M1 - 104576
ER -