Notch signaling plays a critical role in the initiation and progression of various malignancies, and has been targeted therapeutically for several malignancies in clinical trials. Despite the consensus that Notch signaling is deregulated during prostate carcinogenesis, Notch has not yet been employed as a therapeutic target for prostate cancer due to the inadequately defined role of Notch signaling during prostate cancer progression. Our preliminary studies showed that increased expression of the active Notch1 intracellular domain (NICD) in the prostate (the PB-NICD model) promotes prostate luminal epithelial cell proliferation, supporting Notch as a pro-oncogenic pathway in the prostate in vivo. In addition, most Notch signaling components are upregulated in prostate tumor specimens of patients that developed recurrent metastatic diseases. Consistent with this observation, our preliminary studies show that increased Notch activity induces anoikis resistance of prostate epithelial cells and enhances the in vitro and in vivo metastatic potential of prostate cancer cell. Based on these preliminary studies, Notch signaling may promote prostate cancer metastasis. The goals of this application are to determine how Notch signaling alters prostate epithelial cell biology, and to determine whether and how Notch promotes prostate cancer metastasis. To achieve our goals, we will increase Notch activity by manipulating either Notch ligand or receptor in mouse models for human prostate cancer to directly determine whether Notch signaling promotes prostate cancer metastasis. In addition, a combination of genetic, molecular, and cellular biological approaches will be utilized to investigate the molecular mechanisms through which Notch promotes anoikis resistance. Finally, we will perform high-throughput screenings to identify small- molecule compounds that suppress Notch induced anoikis resistance.
Results from this study will provide solid basis for determining whether Notch should be employed as a novel therapeutic target for metastatic prostate cancer, and will have an immediate impact on prostate cancer treatment since diverse agents targeting Notch signaling have already been in clinical trials for other disorders. Our study will generate novel metastatic prostate cancer models that can serve as important tools for preclinical studies. Collectively, this study will contribute substantially towards eliminating death and suffering from prostate cancer.
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| Su, Q; Zhang, B; Zhang, L et al. (2017) Jagged1 upregulation in prostate epithelial cells promotes formation of reactive stroma in the Pten null mouse model for prostate cancer. Oncogene 36:618-627 |
| Su, Qingtai; Xin, Li (2016) Notch signaling in prostate cancer: refining a therapeutic opportunity. Histol Histopathol 31:149-57 |
| Kwon, Oh-Joon; Zhang, Li; Wang, Jianghua et al. (2016) Notch promotes tumor metastasis in a prostate-specific Pten-null mouse model. J Clin Invest 126:2626-41 |
| 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 |
