The cancer stem cell model proposes that a rare subpopulation of cells within a tumor possesses cardinal features of stem cells, namely self-renewal and multipotency, and that these cancer stem cells arise from oncogenic transformation of normal stem cells or related progenitors. Mouse models of prostate carcinoma represent an excellent system in which to explore the implications of this model, and to identify putative cell types of origin for cancer as well as tumor-initiating cells. In previous studies, we have used genetic lineage-tracing in vivo to identify a rare luminal stem cell population marked by expression of the Nkx3.1 homeobox gene (termed CARNs). We have shown that deletion of the Pten tumor suppressor together with activation of Kras in CARNs results in prostate carcinoma, indicating that this cell population is an efficient cell of origin for prostate cancer. Transplantation of CARNs that have undergone deletion of Pten and activation of Kras results in the formation of renal grafts with PIN and carcinoma phenotypes, suggesting that transformed CARNs correspond to tumor-initiating cells. Furthermore, we have identified rare cells expressing NKX3.1 in benign human prostate tissue, revealing the existence of human CARNs. Finally, our lineage-tracing of basal cells indicates that these cells are also a cell of origin for prostate cancer in vivo. Based on these preliminary findings, we will pursue three linked specific aims, using a combination of genetic lineage-tracing and transplantation approaches: (1) Analysis of cell types of origin in vivo to determine whether specific cell epithelial cell types can serve as a cell of origin, and to assess whether different cells of origin may give rise to distinct tumor subtypes. (2) Analysis of tumor-initiation capability from tumors arising from distinct cell origins to determine tumor-initiating cells (TICs) can be identified and whether their frequency differs depending on the cell type of origin. (3) Molecular analysis of CARNs In mouse and human prostate tissue to identify specific markers of transformed CARNs in mice, followed by functional analyses of candidate regulatory genes, and by the identification of human CARN and transformed CARN populations from benign and tumor tissue, in conjunction with Core A. Our proposed studies will be highly synergistic with the analyses of Nkx3.1 regulation of prostate epithelial differentiation and senescence in Project 2, and of the response to DNA damage in prostate epithelial stem cells in Project 3.
Our studies should have significant translational implications through the identification of potential tumor-initiating cells, and by determining whether differences in the cell of origin may be responsible for distinct phenotypes (and possible outcomes) of prostate carcinoma. Furthermore, the identification of markers for putative tumor-initiating cells in human specimens will allow the future evaluation of the cancer stem cell model for human prostate cancer.
|Dutta, Aditya; Panja, Sukanya; Virk, Renu K et al. (2017) Co-clinical Analysis of a Genetically Engineered Mouse Model and Human Prostate Cancer Reveals Significance of NKX3.1 Expression for Response to 5?-reductase Inhibition. Eur Urol 72:499-506
|Zou, Min; Toivanen, Roxanne; Mitrofanova, Antonina et al. (2017) Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer. Cancer Discov 7:736-749
|Zhang, Hailan; Zheng, Tian; Chua, Chee Wai et al. (2016) Nkx3.1 controls the DNA repair response in the mouse prostate. Prostate 76:402-8
|Dutta, Aditya; Le Magnen, Clémentine; Mitrofanova, Antonina et al. (2016) Identification of an NKX3.1-G9a-UTY transcriptional regulatory network that controls prostate differentiation. Science 352:1576-80
|Le Magnen, Clémentine; Dutta, Aditya; Abate-Shen, Cory (2016) Optimizing mouse models for precision cancer prevention. Nat Rev Cancer 16:187-96
|Santanam, Urmila; Banach-Petrosky, Whitney; Abate-Shen, Cory et al. (2016) Atg7 cooperates with Pten loss to drive prostate cancer tumor growth. Genes Dev 30:399-407
|Shen, Michael M (2015) Illuminating the Properties of Prostate Luminal Progenitors. Cell Stem Cell 17:644-646
|Song, Liang-Nian; Silva, Jose; Koller, Antonius et al. (2015) The Tumor Suppressor NKX3.1 Is Targeted for Degradation by DYRK1B Kinase. Mol Cancer Res 13:913-22
|Mitrofanova, Antonina; Aytes, Alvaro; Zou, Min et al. (2015) Predicting Drug Response in Human Prostate Cancer from Preclinical Analysis of In Vivo Mouse Models. Cell Rep 12:2060-71
|Shibata, Maho; Shen, Michael M (2015) Stem cells in genetically-engineered mouse models of prostate cancer. Endocr Relat Cancer 22:T199-208
Showing the most recent 10 out of 34 publications