Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes.
Cell State of Origin Impacts Development of Distinct Endometriosis-Related Ovarian Carcinoma Histotypes.
复制标题
DOI：
10.1158/0008-5472.can-23-1362
复制
发表时间：
2024-01-02
期刊：
影响因子：
11.2
通讯作者：
中科院分区：
文献类型：
--
作者：
两种癌症组织类型从一个共同的起源细胞分化为不同的细胞状态，这突出了考虑细胞状态以更好地理解癌症起源细胞的重要性。透明细胞卵巢癌（CCOC）和子宫内膜样卵巢癌（ENOC）是卵巢癌的组织类型，它们都被认为是由异位子宫内膜（或子宫内膜样）细胞通过子宫内膜异位症中间体引起的。起源相同的细胞类型如何产生两种形态和生物学上不同的组织类型一直令人困惑，特别是考虑到复发性基因突变在两者中都是常见的，并且存在于非恶性前体中。我们通过RNA转录分析发现，在月经周期的分泌期和增殖期，CCOC和ENOC的表达谱与正常子宫内膜相似。雌激素受体（ER）基因（ESR1）启动子上的DNA甲基化在CCOC中富集，这可能潜在地将细胞锁定在分泌状态。与正常分泌型子宫内膜相比，CCOC进一步通过半胱氨酸和谷胱甘肽合成途径基因的表达增加以及铁反转运蛋白的下调来定义，提示铁成瘾，并强调铁下垂是一个潜在的治疗靶点。总的来说，这些发现表明，虽然CCOC和ENOC起源于相同的细胞类型，但这些组织类型可能起源于不同的细胞状态。这种“细胞起源状态”模型可能有助于解释其他器官中出现的组织学和分子癌症亚型的存在。两种癌症组织类型从一个共同的起源细胞分化为不同的细胞状态，这突出了考虑细胞状态以更好地理解癌症起源细胞的重要性。
Two cancer histotypes diverge from a common cell of origin epigenetically locked in different cell states, highlighting the importance of considering cell state to better understand the cell of origin of cancer. Clear cell ovarian carcinoma (CCOC) and endometrioid ovarian carcinoma (ENOC) are ovarian carcinoma histotypes, which are both thought to arise from ectopic endometrial (or endometrial-like) cells through an endometriosis intermediate. How the same cell type of origin gives rise to two morphologically and biologically different histotypes has been perplexing, particularly given that recurrent genetic mutations are common to both and present in nonmalignant precursors. We used RNA transcription analysis to show that the expression profiles of CCOC and ENOC resemble those of normal endometrium at secretory and proliferative phases of the menstrual cycle, respectively. DNA methylation at the promoter of the estrogen receptor (ER) gene (ESR1) was enriched in CCOC, which could potentially lock the cells in the secretory state. Compared with normal secretory-type endometrium, CCOC was further defined by increased expression of cysteine and glutathione synthesis pathway genes and downregulation of the iron antiporter, suggesting iron addiction and highlighting ferroptosis as a potential therapeutic target. Overall, these findings suggest that while CCOC and ENOC arise from the same cell type, these histotypes likely originate from different cell states. This “cell state of origin” model may help to explain the presence of histologic and molecular cancer subtypes arising in other organs. Two cancer histotypes diverge from a common cell of origin epigenetically locked in different cell states, highlighting the importance of considering cell state to better understand the cell of origin of cancer.
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
4
作者：
Yao, Masahiro;Murakami, Takayuki;Shioi, Koichi;Mizuno, Nobuhiko;Ito, Hiroki;Kondo, Keiichi;Hasumi, Hisashi;Sano, Futoshi;Makiyama, Kazuhide;Nakaigawa, Noboru;Kishida, Takeshi;Nagashima, Yoji;Yamanaka, Shoji;Kubota, Yoshinobu
通讯作者：
Kubota, Yoshinobu