Departments of Cell Biology, Oncology, and Biomedical Engineering, Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Baltimore, MD.
Departments of Cell Biology, Oncology, and Biomedical Engineering, Center for Cell Dynamics, The Johns Hopkins University School of Medicine, Baltimore, MD
J Cell Biol. 2018 Oct 1;217(10):3368-3381. doi: 10.1083/jcb.201802144. Epub 2018 Jul 30.
The mammary epithelium is composed of an inner luminal and surrounding myoepithelial cell layer. The presence of cancer cells beyond the myoepithelium defines invasive breast cancer, yet the role of the myoepithelium during invasion remains unclear. We developed a 3D organotypic culture assay to model this process through lineage-specific expression of the prometastatic transcription factor We sought to distinguish the functional role of the myoepithelium in regulating invasion and local dissemination. Myoepithelial-specific expression induced cell-autonomous myoepithelial cell escape. Remarkably, luminal-specific expression was rarely sufficient for escape. Time-lapse microscopy revealed that myoepithelial cells collectively restrain and reinternalize invading Twist1 luminal cells. Barrier function correlated with myoepithelial abundance and required the expression of α-smooth muscle actin and P-cadherin. We next demonstrated that myoepithelial cells can restrain and recapture invasive cancer cells. Our data establish the concept of the myoepithelium as a dynamic barrier to luminal dissemination and implicate both smooth muscle contractility and intercellular adhesion in barrier function.
乳腺上皮由内层腔和周围的肌上皮细胞层组成。癌细胞超出肌上皮的存在定义了浸润性乳腺癌，但肌上皮在浸润过程中的作用仍不清楚。我们开发了一种 3D 器官型培养测定法，通过前转移转录因子的谱系特异性表达来模拟这个过程。我们试图区分肌上皮在调节浸润和局部扩散中的功能作用。肌上皮特异性表达诱导细胞自主肌上皮细胞逃逸。值得注意的是，腔特异性表达很少足以逃逸。延时显微镜揭示了肌上皮细胞集体抑制和再内化入侵的 Twist1 腔细胞。屏障功能与肌上皮细胞的丰度相关，需要α-平滑肌肌动蛋白和 P-钙粘蛋白的表达。我们接下来证明了肌上皮细胞可以抑制和捕获侵袭性癌细胞。我们的数据确立了肌上皮作为腔扩散的动态屏障的概念，并暗示平滑肌收缩性和细胞间黏附在屏障功能中起作用。
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