Podoplanin regulates mammary stem cell function and tumorigenesis by potentiating Wnt/β-catenin signaling
Podoplanin regulates mammary stem cell function and tumorigenesis by potentiating Wnt/β-catenin signaling
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DOI：
10.1242/dev.160382
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发表时间：
2018-02-15
期刊：
影响因子：
4.6
通讯作者：
Deugnier, Marie-Ange
中科院分区：
文献类型：
--
作者：
Bresson, Laura;Faraldo, Marisa M.;Deugnier, Marie-Ange
干细胞（SC）驱动乳腺发育，在出生后产生由腔肌上皮细胞和基底肌上皮细胞组成的上皮双层。SC的失调被认为是某些乳腺癌的起源;然而，SC的分子身份和调节其功能的因子仍然定义不清。我们确定跨膜蛋白podoplanin（Pdpn）作为基底室，包括多能干细胞的特异性标志物，并发现Pdpn定位于基底腔界面。胚胎缺失靶向基底细胞的Pdpn降低了基底和腔SC活性，并影响了基底细胞中几种Wnt/β-连环蛋白信号传导组分的表达。此外，Pdpn丢失减弱了β-连环蛋白诱导的乳腺癌小鼠模型中乳腺肿瘤的形成，限制了肿瘤起始细胞的扩增，并促进了与间充质细胞向上皮细胞转变相关的分子特征。与功能丧失的数据一致，我们证明了Pdpn在机制上增强了乳腺基底细胞中的Wnt/β-连环蛋白信号传导。总的来说，这项研究揭示了Pdpn在乳腺SC功能中的作用，重要的是，将Pdpn鉴定为Wnt/β-连环蛋白信号传导的新调节剂，这是乳腺发育和肿瘤发生的关键途径。
Stem cells (SCs) drive mammary development, giving rise postnatally to an epithelial bilayer composed of luminal and basal myoepithelial cells. Dysregulation of SCs is thought to be at the origin of certain breast cancers; however, the molecular identity of SCs and the factors regulating their function remain poorly defined. We identified the transmembrane protein podoplanin (Pdpn) as a specific marker of the basal compartment, including multipotent SCs, and found Pdpn localized at the basal-luminal interface. Embryonic deletion of Pdpn targeted to basal cells diminished basal and luminal SC activity and affected the expression of several Wnt/beta-catenin signaling components in basal cells. Moreover, Pdpn loss attenuated mammary tumor formation in a mouse model of beta-catenin-induced breast cancer, limiting tumor-initiating cell expansion and promoting molecular features associated with mesenchymal-to-epithelial cell transition. In line with the loss-of-function data, we demonstrated that mechanistically Pdpn enhances Wnt/beta-catenin signaling in mammary basal cells. Overall, this study uncovers a role for Pdpn in mammary SC function and, importantly, identifies Pdpn as a new regulator of Wnt/beta-catenin signaling, a key pathway in mammary development and tumorigenesis.