TY - JOUR
T1 - Developing a novel two-dimensional culture system to enrich human prostate luminal progenitors that can function as a cell of origin for prostate cancer
AU - Zhang, Dingxiao
AU - Lin, Kevin
AU - Lu, Yue
AU - Rycaj, Kiera
AU - Zhong, Yi
AU - Chao, Hsueh Ping
AU - Calhoun-Davis, Tammy
AU - Shen, Jianjun
AU - Tang, Dean G.
N1 - Publisher Copyright:
© 2017 The Authors.
PY - 2017/3
Y1 - 2017/3
N2 - Elucidating the cell of origin of cancer has great significance in stratifying patients into appropriate treatment groups and for developing novel targeted therapies. Early studies demonstrate that only stem-like basal cells in the normal human prostate (NHP) can function as the cell of origin for prostate cancer (PCa). Here,weshow that the organoids derived from bulkNHPluminal cells can also be tumorigenically transformed. Wefurther show that the WIT medium, which is used to culture human mammary epithelial progenitor cells, when combined with the ROCK inhibitor, can readily propagate a population of progenitor-like cells from the primary NHP luminal cell isolates. Such functionally defined luminal progenitors can be transformed by distinct sets of genetic perturbations (i.e., AR+AKT/ ERG or c-MYC+PTEN knockout) to form tumor glands. Genome-wide RNA-Seq analysis of freshly purified unperturbed human benign prostatic basal and luminal cells and culture-expanded lineagespecific stem/progenitor populations reveals that the luminal progenitors possess a distinct gene expression profile that is greatly enriched in advanced, castration-resistant, and metastatic PCa, and it associates with poor patient survival. The ability of the simple two-dimensional culture system reported herein to greatly enrichNHPprogenitor-like cells should facilitate biological and biochemical studies as well as high-throughput screening in these cells and in progenitor-like PCa cells.
AB - Elucidating the cell of origin of cancer has great significance in stratifying patients into appropriate treatment groups and for developing novel targeted therapies. Early studies demonstrate that only stem-like basal cells in the normal human prostate (NHP) can function as the cell of origin for prostate cancer (PCa). Here,weshow that the organoids derived from bulkNHPluminal cells can also be tumorigenically transformed. Wefurther show that the WIT medium, which is used to culture human mammary epithelial progenitor cells, when combined with the ROCK inhibitor, can readily propagate a population of progenitor-like cells from the primary NHP luminal cell isolates. Such functionally defined luminal progenitors can be transformed by distinct sets of genetic perturbations (i.e., AR+AKT/ ERG or c-MYC+PTEN knockout) to form tumor glands. Genome-wide RNA-Seq analysis of freshly purified unperturbed human benign prostatic basal and luminal cells and culture-expanded lineagespecific stem/progenitor populations reveals that the luminal progenitors possess a distinct gene expression profile that is greatly enriched in advanced, castration-resistant, and metastatic PCa, and it associates with poor patient survival. The ability of the simple two-dimensional culture system reported herein to greatly enrichNHPprogenitor-like cells should facilitate biological and biochemical studies as well as high-throughput screening in these cells and in progenitor-like PCa cells.
KW - Cancer cell of origin
KW - Prostate cancer
KW - Prostate epithelial progenitor cells
KW - Stem cells
UR - http://www.scopus.com/inward/record.url?scp=85017527164&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85017527164&partnerID=8YFLogxK
U2 - 10.5966/sctm.2016-0243
DO - 10.5966/sctm.2016-0243
M3 - Article
C2 - 28297567
AN - SCOPUS:85017527164
SN - 2157-6564
VL - 6
SP - 748
EP - 760
JO - Stem Cells Translational Medicine
JF - Stem Cells Translational Medicine
IS - 3
ER -