Endometrial epithelial stem cells and cancer

子宫内膜上皮干细胞与癌症

• 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
• 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

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.

子宫癌是世界上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。 我们虽然肺癌和结肠直肠癌等一些癌症的发病率和死亡率正在下降， 子宫体癌的发病率都在上升。最近广泛的综合基因组分析， 子宫内膜癌提供了重要的见解，剧目的分子畸变 这些恶性肿瘤的特征。他们还确定了子宫内膜癌的四种主要分子亚型， 癌，其特征在于不同的遗传改变和临床行为。然而，利用这一 信息受到损害，因为没有确定起源的小区。通过与干细胞的类比 在其他器官和组织中，子宫内膜上皮干细胞调控机制的异常可能导致 包括癌症在内的一些病理状况。不幸的是，子宫内膜的身份和位置 干细胞仍然没有得到充分的阐明。 最近的一些研究表明，干细胞的位置无论是在腺或腔 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 在子宫内膜腺体的基底段。然而，根据最近的单细胞转录组研究， 在分泌期人子宫内膜中，显示干/祖细胞特征的细胞位于 功能肌的上部区域。其他研究表明子宫内膜上皮可以再生 通过基质/间充质或骨髓细胞来源的干细胞。 我们在PAX 8+细胞中条件性表达荧光报告基因的小鼠中进行的研究支持 假设参与子宫内膜上皮稳态的干细胞位于上皮中 适当的。通过使用单细胞转录组分析，我们已经鉴定了TROP 2（由Tacstd 2编码）和FOXA 2（由Tacstd 2编码）。 分别作为管腔和腺室的可靠标志物。我们的血统轨迹预测， 类器官形成和谱系追踪实验表明，腔上皮和腺上皮都含有 干/祖细胞。TROP 2和FOXA 2也在人子宫内膜上皮中差异表达。 基于以前的发现和我们的初步结果，我们假设子宫内膜上皮含有两个 常驻干/祖细胞池，其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。为了验证这一假设，我们将建立细胞谱系层次结构， 小鼠子宫内膜上皮，测试小鼠腺和腔上皮对恶性肿瘤的敏感性 与浆液性和类浆液性癌常见的改变相关的转化，并建立 小鼠模型发现与人类生物学的相关性。