Endometrial epithelial stem cells and cancer

子宫癌是世界上第四大常见恶性肿瘤，也是导致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， 两者在子宫体癌中的发病率都在增加。最近广泛的综合基因组分析 子宫内膜癌为分子畸变术提供了重要的见解。 以这些恶性肿瘤为特征的。他们还确定了子宫内膜的四种主要分子亚型 癌症，以明显的基因改变和临床行为为特征。然而，这一点的利用 由于来源的细胞(S)尚未确定，信息被泄露。通过与干细胞类比 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 一些病理情况，包括癌症。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位于腺体或腔内。 小鼠子宫内膜上皮的隔室。在人类中，这样的细胞通常被认为位于 位于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 在分泌期人类子宫内膜中，具有干/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。 由基质/间充质干细胞或骨髓细胞来源的干细胞。 我们在小鼠身上进行的研究支持在PAX8+细胞中有条件地表达荧光报告 干细胞参与子宫内膜上皮内稳态的假说定位于上皮 恰到好处。通过单细胞转录组分析，我们已经鉴定出TROP2(由Tacstd2编码)和FOXA2 分别作为腔室和腺室的可靠标志物。我们的血统轨迹预测， 器官形成和谱系追踪实验表明，腔上皮和腺上皮都含有 干细胞/祖细胞。TROP2和FOXA2在人子宫内膜上皮细胞中也有差异表达。 根据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 可能具有不同恶变倾向的常驻干细胞/祖细胞池， 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 小鼠子宫内膜上皮、小鼠腺上皮和腔上皮对恶性病变的敏感性 与浆液性癌和子宫内膜样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。

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.