Our characterization of the Pten null prostate cancer model makes a compelling case that the mutant mouse mimics key features of human prostate cancer development and is a suitable model for investigating the cell- of-origin and cancer stem cells in prostate adenocarcinoma. The goal of this grant application is to test the hypothesis that a specific prostatic cell type is sensitive to the oncogenic transformation and therefore serves as the cell-of-origin of prostate cancer. To the advantage of these investigations, prostate cancer initiation and progression in the Pten mouse model is predictable within a condensed frame, thereby permitting a rapid and systematic study of the cellular, molecular and genetic events linked to tumor development. The Pten model also responds to hormone ablation therapy and develops hormone refractory prostate cancer (HRPC) following prolonged androgen depletion. We will first decipher the prostate epithelial stem-progenitor cell hierarchy under normal physiological conditions and then use this hierarchy map to identify cancer stem cells in the murine prostate cancer models and human prostate cancer samples (Aim 1). We will further address the cellular and molecular basis of HRPC. In particular, the link between androgen-independent growth and cancer stem cells will be carefully examined. With characterized cancer stem cells in hand, we will then investigate the molecular mechanisms underlying prostate cancer stem cell development, including pathways controlling stem cell self- renewal and differentiation, and test the effects of small pathway-specific inhibitors on cancer stem cells and HRPC development (Aim 2). We expect that the identification and functional characterization of both the cell- of-origin of prostate cancer as well as dysregulated signaling pathways will provide essential information for improved detection, diagnosis, and therapy of this disease. Although focused on prostate cancer, the studies outlined here and the mechanisms elucidated in this proposal will be broadly relevant, since PTEN is expressed in all cell types in the human body and PTEN mutations are observed in a variety of human cancers.

Public Health Relevance

Despite its enormous impact on male health, the molecular mechanisms underlying the pathogenesis of prostate cancer remain unsolved. A central focus of this application is to characterize the prostate cancer stem cells and to test whether altered stem cell properties may contribute to prostate cancer development and hormone refractory prostate cancer development. This will help in understanding the origin of the disease and provide rationales for novel, stem cell-targeted treatment.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Ogunbiyi, Peter
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Ruscetti, M; Dadashian, E L; Guo, W et al. (2016) HDAC inhibition impedes epithelial-mesenchymal plasticity and suppresses metastatic, castration-resistant prostate cancer. Oncogene 35:3781-95
Ruscetti, Marcus; Quach, Bill; Dadashian, Eman L et al. (2015) Tracking and Functional Characterization of Epithelial-Mesenchymal Transition and Mesenchymal Tumor Cells during Prostate Cancer Metastasis. Cancer Res 75:2749-59
Garcia, Alejandro J; Ruscetti, Marcus; Arenzana, Teresita L et al. (2014) Pten null prostate epithelium promotes localized myeloid-derived suppressor cell expansion and immune suppression during tumor initiation and progression. Mol Cell Biol 34:2017-28
Hübner, Anette; Mulholland, David J; Standen, Claire L et al. (2012) JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate. Proc Natl Acad Sci U S A 109:12046-51
Schlacher, Katharina; Wu, Hong; Jasin, Maria (2012) A distinct replication fork protection pathway connects Fanconi anemia tumor suppressors to RAD51-BRCA1/2. Cancer Cell 22:106-16
Jiao, Jing; Hindoyan, Antreas; Wang, Shunyou et al. (2012) Identification of CD166 as a surface marker for enriching prostate stem/progenitor and cancer initiating cells. PLoS One 7:e42564
Mulholland, David J; Kobayashi, Naoko; Ruscetti, Marcus et al. (2012) Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res 72:1878-89
Tran, Linh M; Chang, Chun-Ju; Plaisier, Seema et al. (2012) Determining PTEN functional status by network component deduced transcription factor activities. PLoS One 7:e31053
Schlacher, Katharina; Christ, Nicole; Siaud, Nicolas et al. (2011) Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145:529-42
Mulholland, David J; Tran, Linh M; Li, Yunfeng et al. (2011) Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 19:792-804

Showing the most recent 10 out of 16 publications