Endometrial epithelial stem cells and cancer

子宫内膜上皮干细胞与癌症

基本信息

批准号：
10621932
负责人：
Alexander Y Nikitin
金额：
$ 42.52万
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：
2021-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621932
关键词：
Adjuvant Therapy Adult Behavior Biological Biological Markers Body of uterus Bone Marrow Cells Cancer Etiology Carcinoma Cell Differentiation process Cell Lineage Cells Cessation of life Characteristics Clinical Colorectal Cancer Endometrial Endometrial Carcinoma Endometrioid Carcinoma Endometrium Ensure Epithelial Cells Epithelium Estrogen Replacement Therapy Estrous Cycle Foundations Future Gene Modified Genomics Gland Homeostasis Human Human Biology Incidence Individual Indolent Infertility Link Location Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Mesenchymal Molecular Molecular Abnormality Mus Mutation Natural regeneration Neoplasms Organ Organoids Pathogenesis Pathologic Phase Phenotype Physiological Population Predisposition Proliferating Recurrence Reporter Reproductive Biology Reproductive History Role Serous Solid Stratification Stromal Cells Supporting Cell System TP53 gene Testing Time Tissues Uterine Cancer Uterus Vascularization Woman Work Xenograft procedure aged cancer type cell type clinically relevant differential expression endometrial organoid endometriosis epithelial stem cell epithelium regeneration experimental study improved insight molecular subtypes mortality mouse model older women single-cell RNA sequencing stem cell self renewal stem cells therapeutic target therapeutically effective tissue stem cells transcriptome translational study tumor

项目摘要

Uterine cancer is the 4th most frequent malignancy and the 6th cause of cancer-related deaths in women in the US. While the incidence and mortality rates of some cancers, such as lung and colorectal cancers, are declining, they are both increasing for cancers of the uterine corpus. Recent extensive integrated genomic analyses of endometrial carcinomas have provided important insights into the repertoire of molecular aberrations characteristic of these malignancies. They have also identified four major molecular subtypes of endometrial carcinoma, characterized by distinct genetic alterations and clinical behavior. However, utilization of this information is compromised because the cell(s) of origin have not been determined. By analogy with stem cells in other organs and tissues, aberrations in mechanisms governing endometrial epithelial stem cells may lead to a number of pathological conditions, including cancer. Unfortunately, the identity and location of endometrial stem cells remains insufficiently elucidated. A number of recent studies have suggested location of stem cells either in the glandular or luminal compartments of the mouse endometrial epithelium. In humans, such cells are commonly thought to be located in the basalis segment of the endometrial glands. However, according to a recent single cell transcriptome study of secretory phase human endometrium, cells showing characteristics of stem/progenitor cells are located in the upper region of the functionalis. Other studies have suggested that endometrial epithelium can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Our studies performed in mice conditionally expressing fluorescent reporters in PAX8+ cells support the hypothesis that stem cells involved in the homeostasis of endometrial epithelium are located in the epithelium proper. By using single cell transcriptome analysis, we have identified TROP2 (encoded by Tacstd2) and FOXA2 as reliable markers of luminal and glandular compartments, respectively. Our lineage trajectory predictions, organoid formation and lineage tracing experiments suggest that both luminal and glandular epithelium contain stem/progenitor cells. TROP2 and FOXA2 are also differentially expressed in human endometrial epithelium. Based on previous findings and our preliminary results we hypothesize that endometrial epithelium contains two pools of resident stem/progenitor cells, which may have different propensities for malignant transformation, thereby leading to clinically distinct neoplasms. To test this hypothesis, we will establish cell lineage hierarchy of the mouse endometrial epithelium, test susceptibility of the mouse glandular and luminal epithelium to malignant transformation associated with alterations common for serous and endometrioid carcinomas, and establish the relevance of mouse model findings to human biology.

子宫癌是女性第四大最常见的恶性肿瘤，也是女性癌症相关死亡的第六大原因。我们。虽然肺癌和结直肠癌等一些癌症的发病率和死亡率正在下降，子宫体癌症的发病率都在增加。最近广泛的综合基因组分析子宫内膜癌为分子畸变的全部提供了重要的见解这些恶性肿瘤的特征。他们还确定了子宫内膜的四种主要分子亚型癌症，其特征是独特的基因改变和临床行为。然而，利用这一由于细胞来源尚未确定，信息受到损害。与干细胞类比在其他器官和组织中，控制子宫内膜上皮干细胞的机制异常可能会导致许多病理状况，包括癌症。不幸的是，子宫内膜的身份和位置干细胞的阐明仍不充分。最近的许多研究表明干细胞位于腺体或管腔中小鼠子宫内膜上皮的隔室。在人类中，这种细胞通常被认为位于在子宫内膜腺的基底段。然而，根据最近的一项单细胞转录组研究在人子宫内膜分泌期，表现出干细胞/祖细胞特征的细胞位于泛函上部区域。其他研究表明子宫内膜上皮可以再生由基质/间充质或骨髓细胞来源的干细胞产生。我们在 PAX8+ 细胞中条件表达荧光报告基因的小鼠中进行的研究支持了假设干细胞参与子宫内膜上皮的稳态，位于上皮细胞中恰当的。通过使用单细胞转录组分析，我们鉴定了TROP2（由Tacstd2编码）和FOXA2 分别作为腔室和腺室的可靠标记。我们的谱系轨迹预测，类器官形成和谱系追踪实验表明，管腔上皮和腺上皮都含有干/祖细胞。 TROP2 和 FOXA2 在人子宫内膜上皮中也有差异表达。根据之前的发现和我们的初步结果，我们假设子宫内膜上皮包含两种常驻干细胞/祖细胞池，可能具有不同的恶性转化倾向，从而导致临床上不同的肿瘤。为了检验这个假设，我们将建立细胞谱系层次结构小鼠子宫内膜上皮，测试小鼠腺体和管腔上皮对恶性的敏感性与浆液性癌和子宫内膜样癌常见改变相关的转化，并建立小鼠模型研究结果与人类生物学的相关性。