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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肿瘤。虽然早期的治疗方法是有效的