This grant application aims to understand basic biology of prostate epithelial differentiation. Mammalian tissues are composed of cells organized in a hierarchical manner, including stem cels, committed progenitors, and terminally differentiated cells. Dissecting the tissue lineage hierarchy will help identify molecular signaling pathways that play key roles in development and diseases. The prostate epithelial lineage hierarchy remains largely undefined. Though two distinct types of multipotent prostate stem cells have been identified, it remains unclear how stem cells differentiate and generate terminally differentiated cell lineages. This grant proposal is focused on the general question of how prostate stem cells give rise to prostate luminal epithelial cells that constitutes more than 90% of prostate epithelia. Our goals are to investigate how the prostate luminal cell lineage is sustained and what the roles are of the androgen receptor in different epithelial cell lineages along epithelial cell differentiation. Our preliminary data suggest that luminal cells are phenotypically and functionally heterogeneous and support the long-existing hypothesis of the existence of a population of androgen- independent prostate luminal progenitors. Using a combination of genetic and cellular approaches, we will (1) determine how the prostate luminal cell lineage is sustained in vivo;(2) isolate prostate luminal progenitor cells based on their antigenic expression profiles;(3) investigate the biological role of the androgen receptor in different prostate epithelial cell lineages.
Prostate related diseases, including benign prostatic hyperplasia and prostate cancer, represent major health problems for men. Our proposed studies are important prerequisites to unveil molecular signaling pathways that play critical roles in initiation and progression of these diseases, and will eventually have a major impact on their diagnosis and therapeutics.
|Kwon, Oh-Joon; Zhang, Li; Xin, Li (2016) Stem Cell Antigen-1 Identifies a Distinct Androgen-Independent Murine Prostatic Luminal Cell Lineage with Bipotent Potential. Stem Cells 34:191-202|
|Zhang, Boyu; Kwon, Oh-Joon; Henry, Gervaise et al. (2016) Non-Cell-Autonomous Regulation of Prostate Epithelial Homeostasis by Androgen Receptor. Mol Cell 63:976-89|
|Kwon, Oh-Joon; Valdez, Joseph M; Zhang, Li et al. (2014) Increased Notch signalling inhibits anoikis and stimulates proliferation of prostate luminal epithelial cells. Nat Commun 5:4416|
|Kwon, Oh-Joon; Zhang, Li; Ittmann, Michael M et al. (2014) Prostatic inflammation enhances basal-to-luminal differentiation and accelerates initiation of prostate cancer with a basal cell origin. Proc Natl Acad Sci U S A 111:E592-600|
|Xin, Li (2013) A developmental stage-dependent switch of the mechanisms for prostate epithelial maintenance. Asian J Androl 15:85-6|
|Xin, L (2013) Cells of origin for cancer: an updated view from prostate cancer. Oncogene 32:3655-63|
|Choi, Nahyun; Zhang, Boyu; Zhang, Li et al. (2012) Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell 21:253-65|
|Valdez, Joseph M; Zhang, Li; Su, Qingtai et al. (2012) Notch and TGFÎ² form a reciprocal positive regulatory loop that suppresses murine prostate basal stem/progenitor cell activity. Cell Stem Cell 11:676-88|
|Zhang, Li; Zhang, Boyu; Han, Sang Jun et al. (2012) Targeting CreER(T2) expression to keratin 8-expressing murine simple epithelia using bacterial artificial chromosome transgenesis. Transgenic Res 21:1117-23|