Cancer-prone cell states of the fallopian tubal epithelium

输卵管上皮细胞的易癌状态

• 批准号: 10397606
• 负责人: Alexander Y Nikitin
• 金额: $ 42.09万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397606
• 关键词: Biological; Breast Carcinoma; Carcinoma; Cell Lineage; Cells; Characteristics; Charge; Clinical; Consensus; Data; Diagnosis; Disease; Dissociation; Distal; Epithelial; Epithelial Cells; Epithelial ovarian cancer; Frequencies; Genetic Transcription; Genomics; Growth Factor; Heterogeneity; Human; Implant; Inflammatory; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mechanics; Mesenchymal; Modality; Molecular Abnormality; Molecular Profiling; Morphology; Mus; Mutation; Natural regeneration; Neoplasm Metastasis; Organoids; Ovarian; Ovarian Carcinoma; Patients; Population; Predisposition; Prognostic Marker; Prostate carcinoma; Reporting; Role; Serous; Signal Transduction; Stratification; Stromal Cells; Stromal Change; Surface; Survival Rate; Symptoms; System; Testing; Tube; Woman; base; biomarker development; cancer cell; cancer type; cell type; cellular development; diagnostic biomarker; genetic signature; immunoreactivity; insight; mutant; novel therapeutics; response; stem; stem cells; transcriptome; transcriptomics; treatment response; tumor

Project Summary Ovarian/extra-uterine high-grade serous carcinoma (HGSC) is the most common and aggressive type of ovarian cancer. It often has no symptoms at early stages and over 80% of patients are diagnosed at advanced, usually incurable, cancer stages, when the tumors have already metastasized. Extensive integrated genomic analysis allowed identification of several clinically distinct subtypes of HGSC. A significant fraction of HGSC arises from the tubal epithelium (TE) located in the distal region of Fallopian tube (aka uterine tube or oviduct). Recent single cell transcriptome analysis of distal TE inferred that HGSC heterogeneity could be connected to diverse cell states present in TE cell lineages. Unfortunately, precise cell lineage-based hierarchy of identified TE cell types has not been yet established. Furthermore, cancer-prone cellular states of TE are insufficiently defined and factors influencing such states remain unclear. Thus, it remains unknown if uneven clinical course of HGSC and development of cellular therapeutic responses may reflect different modes of initiation and progression of this malignancy. Our preliminary studies show that, in addition to known secretory (OVGP1+) and ciliated (FOXJ1+, CD24+) epithelial cells, there are several epithelial cell populations characterized by preferential expression of stem/progenitor cell markers, such as SLC1A3, CD49f (ITGA6), and KLF6. A Monocle cell-lineage trajectory prediction analysis of our single-cell transcriptomic data identified a population of SLC1A3+ stem/progenitor cells that give rise to both secretory and ciliated cells by progressing through transient intermediates, including a KRT5+ cell population. This prediction has been confirmed by lineage tracing of SLC1A3+ cells and ex vivo studies. Cells in a transient state (CD24med CD49f+) form spheres in consecutive rounds of sphere dissociation- regeneration and express KRT5. Under normal homeostatic conditions, KRT5+ cells are largely dormant and minimally contribute to secretory and ciliated cell lineages. However, KRT5+ cells become actively involved in re-epithelialization after mechanical damage. Our preliminary results suggest that stromal charges begin to co- evolve with mutant epithelial cells before the earliest morphologically detectable alterations. Based on previous studies and our preliminary results we hypothesize that cancer-prone TE cell states are determined by levels of epithelial damage and stromal milieu changes. To test this hypothesis we propose (1) to establish the role of specific cell states during homeostatic and posttraumatic regeneration, (2) to determine the impact of epithelial damage on cancer susceptibility of epithelial states and (3) to identify and characterize epithelial and stromal cell lineage dynamics during early stages of TE malignant transformation.

项目摘要 卵巢/外部高级浆液性癌（HGSC）是最常见和侵略性的卵巢 癌症。它通常在早期没有症状，并且在晚期诊断出80％以上的患者，通常 肿瘤已经转移时无法治愈的癌症阶段。广泛的综合基因组分析 允许鉴定HGSC的几种临床上不同的亚型。 HGSC的很大一部分来自 位于输卵管远端区域（又名子宫管或卵形）的管上皮（TE）。最近的单曲 远端TE的细胞转录组分析推断，HGSC异质性可以连接到多种细胞 存在于细胞谱系中的状态。不幸的是，确定的TE细胞类型的精确基于细胞谱系的层次结构 尚未建立。此外，易于癌症的TE的细胞状态不足以定义，并且 影响这种状态的因素尚不清楚。因此，尚不清楚HGSC和 细胞治疗反应的发展可能反映出不同的起始和进展方式 恶性。我们的初步研究表明，除了已知分泌（OVGP1+）和纤毛（FoxJ1+， CD24+）上皮细胞，有几个上皮细胞种群，其特征是以优先表达 茎/祖细胞标记，例如SLC1A3，CD49F（ITGA6）和KLF6。单片细胞单线轨迹 单细胞转录组数据的预测分析确定了SLC1A3+茎/祖细胞的群体 通过瞬态中间体进行，包括A KRT5+细胞种群。通过SLC1A3+细胞的谱系跟踪和Ex Vivo证实了这一预测 研究。在连续的球体解离 - 再生和Express KRT5。在正常的稳态条件下，KRT5+细胞在很大程度上处于休眠状态，并且 最小化有助于分泌和纤毛的细胞谱系。但是，KRT5+细胞积极参与 机械损伤后重新上皮化。我们的初步结果表明，基质电荷开始共同 在最早的形态学检测到的变化之前，用突变的上皮细胞进化。基于以前的 研究和我们的初步结果，我们假设容易发生癌症的细胞状态取决于 上皮损害和基质环境变化。为了检验这一假设，我们建议（1）确定 稳态和创伤后再生期间的特定细胞态，（2）确定上皮的影响 上皮状态的癌症易感性的损害以及（3）识别和表征上皮和基质细胞的损害 在TE恶性转化的早期阶段的谱系动力学。