Cancer-prone cell states of the fallopian tubal epithelium

输卵管上皮细胞的易癌状态

基本信息

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
项目类别：
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

项目摘要

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.

项目概要卵巢/子宫外高级浆液性癌 (HGSC) 是最常见且最具侵袭性的卵巢类型癌症。早期通常没有任何症状，超过 80% 的患者确诊时已是晚期，通常无法治愈的癌症阶段，此时肿瘤已经转移。广泛的整合基因组分析允许鉴定几种临床上不同的 HGSC 亚型。 HGSC 的很大一部分来自输卵管上皮 (TE) 位于输卵管（又称子宫管或输卵管）远端区域。最近单曲远端 TE 的细胞转录组分析推断 HGSC 异质性可能与不同的细胞有关 TE 细胞谱系中存在的状态。不幸的是，已识别的 TE 细胞类型基于精确的细胞谱系层次结构尚未成立。此外，TE 的癌症倾向细胞状态尚未得到充分定义和影响这些状态的因素仍不清楚。因此，目前尚不清楚 HGSC 的临床过程是否不均匀细胞治疗反应的发展可能反映了这种治疗反应的不同启动和进展模式恶性肿瘤。我们的初步研究表明，除了已知的分泌型 (OVGP1+) 和纤毛型 (FOXJ1+) CD24+）上皮细胞，有几种上皮细胞群的特征是优先表达干/祖细胞标记物，例如 SLC1A3、CD49f (ITGA6) 和 KLF6。 Monocle 细胞谱系轨迹我们的单细胞转录组数据的预测分析确定了 SLC1A3+ 干/祖细胞群体通过瞬时中间体产生分泌细胞和纤毛细胞，包括 KRT5+ 细胞群。这一预测已通过 SLC1A3+ 细胞的谱系追踪和离体实验得到证实。研究。处于瞬时状态的细胞（CD24med CD49f+）在连续几轮球体解离中形成球体- 再生并表达KRT5。在正常稳态条件下，KRT5+ 细胞大部分处于休眠状态，对分泌细胞和纤毛细胞谱系的贡献最小。然而，KRT5+ 细胞积极参与机械损伤后的上皮再形成。我们的初步结果表明基质电荷开始共同作用在最早的形态学可检测的改变之前与突变的上皮细胞一起进化。基于之前的研究和我们的初步结果我们假设易患癌症的 TE 细胞状态是由上皮损伤和基质环境变化。为了检验这个假设，我们建议（1）建立稳态和创伤后再生期间的特定细胞状态，（2）确定上皮细胞的影响对上皮状态癌症易感性的损害以及（3）识别和表征上皮细胞和基质细胞 TE 恶性转化早期阶段的谱系动态。