Precancer Niche Formation in the Fallopian Tube

输卵管癌前生态位的形成

基本信息

批准号：
9890809
负责人：
SANDRA ORSULIC
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9890809
关键词：
3-Dimensional Affect Atypia BRCA1 Mutation BRCA1 gene Bioinformatics Biological Markers CDC2 gene Cancer Detection Cancerous Cell Cycle Cell Death Cell Polarity Cell Proliferation Cell Separation Cell Survival Cells Characteristics Collection DNA Damage DNA Repair DNA Sequence Alteration Data Development Early Diagnosis Environment Epithelial Epithelium Equilibrium Event Excision Follicular Fluid Genes Genetic Genomic Instability Genotoxic Stress Growth Factor Health Resources Histologic Hormonal Change Hormones Human Image Lead Lesion Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of ovary Mammalian Oviducts Modeling Molecular Molecular Analysis Morphology Mus Operative Surgical Procedures Organoids Outcome Ovarian Serous Adenocarcinoma Ovary Ovulation PTEN gene Pathway interactions Patients Personal Satisfaction Pharmacology Policy Maker Populations at Risk Postmenopause Preclinical Testing Prevention Process Progesterone Research Resources Risk Role Sampling Screening for cancer Secretory Cell Signal Transduction Specimen Stratification Stress Subgroup Symptoms TP53 gene Test Result Testing Therapeutic Tumor Suppressor Genes United States Veterans Woman biomarker development biomarker identification cancer cell cancer initiation cancer prevention cell injury cell transformation clinical practice clinically relevant convolutional neural network curative treatments deep neural network early detection biomarkers early onset gene function high risk image processing in vivo induced pluripotent stem cell inhibitor/antagonist malignant breast neoplasm mortality mouse model mutant mutation carrier ovarian cancer prevention overexpression prevent response screening segregation specific biomarkers survivin tool transcriptome sequencing transcriptomics tumor growth

项目摘要

Background: Ovarian cancer is the most fatal gynecologic cancer. While curative treatments exist for early- stage cancers, there is a lack of specific biomarkers for detecting preneoplastic lesions, which usually occur in the fallopian tube epithelia (FTE). Normal FTE consists of small clusters of secretory and ciliated cells intermixed in an approximately 1:1 ratio. Although the mechanism of FTE transformation is not fully understood, it is believed that hormones and growth factors in the follicular fluid expose FTE to genotoxic stress during ovulation and that escape from the stress-induced cell death leads to an aberrant accumulation of secretory cells. In this microenvironment, secretory cells sometimes undergo genetic and morphologic changes that include stratification, atypia, and loss of cell polarity, which are considered the precursor lesions to ovarian cancer. Aberrant secretory cell accumulation is associated with an increased risk of ovarian cancer and is more common in women with germline BRCA1 mutations. However, the morphologic changes and molecular mechanisms that lead to secretory cell transformation are unknown. Specifically, the role of ciliated cells in the formation of precursor FTE lesions is unknown. Preliminary data: Our histologic and molecular analyses of FTE from BRCA1 mutation carriers and non-carriers revealed that postmenopausal BRCA1 mutation carriers have a higher ratio of secretory to ciliated cells and increased levels of the cell survival-associated genes CDK1 and Survivin, suggesting that secretory cells escape cell death. Unexpectedly, we observed that homotypic cell segregation and loss of ciliated cells precede secretory cell accumulation. Hypothesis: We propose that homotypic cell signaling and loss of ciliated cells create a favorable microenvironment for secretory cell transformation in BRCA1 mutant FTE providing that other conditions, such as hormonal changes and genotoxic stress, coincide and tip the balance toward uncontrolled proliferation. Unique resources: We are the first group to differentiate induced pluripotent stem cells (iPSCs) into FTE and establish iPSC organoids from BRCA1 mutation carriers and non-carriers. We have one of the largest collections of FTE specimens with detailed clinicopathologic and demographic data from high-risk patients. We will leverage our recently developed computational imaging convolutional neural networks pipeline for extraction of “hidden” preneoplastic characteristics for biomarker development and identification of potential targets for prevention. Specific Aims: In Aim 1, we will use human and mouse FTE organoids and in vivo mouse models to test the hypothesis that ciliated cells protect secretory cells from genotoxic stress. In Aim 2, we will test the hypothesis that aberrant secretory cell survival under genotoxic stress can be counteracted by pharmacologic inhibitors of genes involved in cell survival, such as CDK1 and Survivin. In Aim 3, we will integrate RNA sequencing and image processing with deep-neural network learning to identify clinically-relevant molecular and histomorphometric biomarkers of preneoplastic lesions in fallopian tubes from BRCA1 mutation carriers. Impact: This research will lead to a better understanding of the interplay between predisposing genetic mutations and the microenvironmental changes that precede ovarian cancer initiation. Identifying potential molecular and morphometric contributors to the formation of the precancer niche will assist in the development of new strategies for ovarian cancer prevention and detection, which are urgently needed in clinical practice.

背景：卵巢癌是最致命的妇科癌症，而早期卵巢癌已有治疗方法。在癌症分期中，缺乏用于检测癌前病变的特异性生物标志物，这些病变通常发生在输卵管上皮 (FTE) 正常 FTE 由混合的分泌细胞和纤毛细胞小簇组成。虽然 FTE 转化的机制尚未完全清楚，但据信。卵泡液中的激素和生长因子使 FTE 在排卵期间面临基因毒性应激，并且逃避应激诱导的细胞死亡会导致分泌细胞异常积累。在微环境中，分泌细胞有时会发生遗传和形态变化，包括分层、异型性和细胞极性丧失，这些被认为是卵巢癌的前兆病变。异常的分泌细胞积聚与卵巢癌风险增加相关，并且更为常见然而，在具有种系 BRCA1 突变的女性中，形态学变化和分子机制。具体而言，纤毛细胞在形成中的作用尚不清楚。前兆 FTE 病变尚不清楚。初步数据：我们对 BRCA1 突变携带者和非携带者的 FTE 进行组织学和分子分析研究表明，绝经后 BRCA1 突变携带者的分泌细胞与纤毛细胞的比例较高，细胞存活相关基因 CDK1 和 Survivin 水平升高，表明分泌细胞逃逸出乎意料的是，我们观察到同型细胞分离和纤毛细胞的损失先于细胞死亡。分泌细胞积累。假设：我们认为同型细胞信号传导和纤毛细胞的损失创造了有利的 BRCA1 突变体 FTE 中分泌细胞转化的微环境提供了其他条件，例如当荷尔蒙变化和基因毒性应激同时发生时，平衡就会朝着不受控制的增殖方向倾斜。独特的资源：我们是第一个将诱导多能干细胞（iPSC）分化为 FTE 和从 BRCA1 突变携带者和非携带者建立 iPSC 类器官我们拥有最大的收集品之一。我们将利用来自高风险患者的详细临床病理学和人口统计数据的 FTE 样本。我们最近开发的计算成像卷积神经网络管道用于提取“隐藏” 用于生物标志物开发和识别潜在预防目标的肿瘤前特征。具体目标：在目标 1 中，我们将使用人类和小鼠 FTE 类器官以及体内小鼠模型来测试纤毛细胞保护分泌细胞免受基因毒性应激的假设在目标 2 中，我们将检验该假设。遗传毒性应激下异常的分泌细胞存活可以通过药物抑制剂来抵消与细胞存活相关的基因，例如 CDK1 和 Survivin 在目标 3 中，我们将整合 RNA 测序和通过深度神经网络学习进行图像处理，以识别临床相关的分子和 BRCA1 突变携带者输卵管癌前病变的组织形态学生物标志物。影响：这项研究将有助于更好地理解易感基因突变之间的相互作用以及卵巢癌发生前的微环境变化。癌前生态位形成的形态学贡献者将有助于制定新策略用于卵巢癌的预防和检测，这是临床实践中迫切需要的。