Université de Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, Institut de Biologie de Lille, 1 rue du Professeur Calmette, CS 54447, Lille Cedex 59000/59021, France.
Université de Lille, INSERM U908 - CPAC - Cell Plasticity and Cancer, Lille 59000, France.
Stem Cell Reports. 2019 Jul 9;13(1):10-20. doi: 10.1016/j.stemcr.2019.05.013. Epub 2019 Jun 13.
During normal mammary gland development, s-SHIP promoter expression marks a distinct type of mammary stem cells, at two different stages, puberty and early mid-pregnancy. To determine whether s-SHIP is a marker of mammary cancer stem cells (CSCs), we generated bitransgenic mice by crossing the C3(1)-SV40 T-antigen transgenic mouse model of breast cancer, and a transgenic mouse (11.5kb-GFP) expressing green fluorescent protein from the s-SHIP promoter. Here we show that in mammary tumors originating in these bitransgenic mice, s-SHIP promoter expression enriches a rare cell population with CSC activity as demonstrated by sphere-forming assays in vitro and limiting dilution transplantation in vivo. These s-SHIP-positive CSCs are characterized by lower expression of Delta-like non-canonical Notch ligand 1 (DLK1), a negative regulator of the Notch pathway. Inactivation of Dlk1 in s-SHIP-negative tumor cells increases their tumorigenic potential, suggesting a role for DLK1 in mammary cancer stemness.
在正常乳腺发育过程中，s-SHIP 启动子表达标志着两种不同阶段（青春期和早孕）的一种独特的乳腺干细胞。为了确定 s-SHIP 是否是乳腺癌症干细胞（CSC）的标志物，我们通过将 C3(1)-SV40 T 抗原转基因乳腺癌小鼠模型与表达绿色荧光蛋白的 s-SHIP 启动子转基因小鼠（11.5kb-GFP）杂交，生成了双转基因小鼠。在这里，我们表明在源自这些双转基因小鼠的乳腺肿瘤中，s-SHIP 启动子表达富集了具有 CSC 活性的罕见细胞群体，这通过体外球体形成测定和体内有限稀释移植得到证实。这些 s-SHIP 阳性 CSC 的特征是 Notch 通路的负调节剂 Delta-like 非经典 Notch 配体 1（DLK1）的表达较低。在 s-SHIP 阴性肿瘤细胞中失活 Dlk1 会增加其致瘤潜能，提示 DLK1 在乳腺癌症干细胞特性中发挥作用。
