The Molecular Systems Pathology Core will provide expert morphological evaluation of normal and tumor samples of human and mouse models to investigators of the Program Project. The Core will further develop novel technology in the areas of morphometry and image analysis of quantitative biomarker multiplexing in tissue sections. This Core is also generating new assays, such as those for analysis of DNA damage using H2AX quantitation at high spectral resolution, for studying senescence at the microanatomical detail, and ex vivo assays using fresh human prostate cancer specimens. Through such approaches, the Core will integrate with all three Projects in pursuing systems pathology approaches to investigate expression of NKX3.I (the major scientific goal of the Core), to study markers of prostate stem cells (Project 1), to examine the expression of direct transcriptional targets of NKX3.1 (Project 2), and to quantify DNA damage response markers in human and mouse prostate tissues (Project 3). We have ample tissue resources to assist all Projects, including a set of 140 human prostate tumors (training set), a second independent cohort of 410 human prostate tumors (validation set), as well as large and well characterized cohorts of human prostate cancer tissues from Memorial Sloan-Kettering Cancer Center (MSKCC) and the Genitourinary Program of the Southwestern Oncology Group (GU-SWOG). This Core also provides assistance in conducting immunohistochemical (IHC) and in situ hybridization (ISH) assays, including interphase fluorescence in situ hybridization (FISH). Using these resources, we will characterize expression patterns of known genes participating in pathways of relevance for the Program, as well as novel genes identified through studies conducted by the proposed projects.
The specific aims are: (1) To investigate the occurrence and correlation of molecular alterations associated with prostate cancer initiation in human preneoplastic and tumor lesions, an aim that includes both technology development and further definition of the temporal map of molecular alterations associated with prostate cancer progression; (2) To examine the expression of NKX3.1 and stem/progenitor markers in androgen-ablated and hormonally-intact human prostate specimens, working with Michael Shen in Project 1; (3) To characterize the expression of NKX3.1 and its transcriptional targets identified in Project 2 using normal and tumor human specimens, working with Cory Abate-Shen; and (4) To further study the relationship of NKX3.I inactivation and the formation of TMPRSS2-ERG fusions, studying pre- and post-treated mice after DNA damage with Edward Gelmann in Project 3.

Public Health Relevance

This Core will promote outstanding translational research on molecular mechanisms of prostate cancer initiation and progression by providing technical support and tissue resources aimed at characterizing genetic aberrations and altered expression of genes involved in such processes. Critical to this Program, and to the scientific community, is the implementation of novel assays through innovative developments in tissue morphometry and quantitative biomarker multiplexing that this Core is also pursuing.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-0 (O1))
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Columbia University (N.Y.)
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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

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