Molecular Systems Pathology Core

分子系统病理学中心将为该项目的研究人员提供人类和小鼠模型的正常和肿瘤样本的专家形态学评估。Core将进一步开发组织切片中定量生物标志物多路复用的形态测量和图像分析领域的新技术。该核心还产生了新的检测方法，例如使用H2 AX定量在高光谱分辨率下分析DNA损伤，用于研究微观解剖细节的衰老，以及使用新鲜人类前列腺癌标本的离体检测。通过这些方法，核心将与所有三个项目整合，采用系统病理学方法研究NKX3.I的表达（核心的主要科学目标），研究前列腺干细胞的标志物（项目1），检查NKX3.1的直接转录靶点的表达（项目2），并量化人类和小鼠前列腺组织中的DNA损伤反应标志物（项目3）。我们有充足的组织资源来协助所有项目，包括一组140例人类前列腺肿瘤（训练集），第二组410例人类前列腺肿瘤（验证集），以及来自纪念斯隆-凯特琳癌症中心（MSKCC）和西南肿瘤学组（GU-SWOG）泌尿生殖系统项目的大型且特征良好的人类前列腺癌组织队列。该核心还可协助进行免疫组织化学（IHC）和原位杂交（ISH）检测，包括间期荧光原位杂交（FISH）。利用这些资源，我们将表征参与该计划相关途径的已知基因的表达模式，以及通过拟议项目进行的研究确定的新基因。具体目标是：（1）研究在人肿瘤前病变和肿瘤病变中与前列腺癌起始相关的分子改变的发生和相关性，该目的包括技术开发和进一步定义与前列腺癌进展相关的分子改变的时间图;（2）检测NKX3.1和干/祖细胞标志物在雄激素消融和前列腺完整的人前列腺标本中的表达，（3）与Cory Abate-Shen合作，使用正常和肿瘤人类标本表征项目2中鉴定的NKX3.1及其转录靶点的表达;和（4）为了进一步研究NKX3.I失活与TMPRSS 2-ERG融合体形成的关系，在项目3中与Edward Gelmann一起研究DNA损伤后治疗前和治疗后的小鼠。

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.