Division of Molecular Pathology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nat Commun. 2019 Aug 23;10(1):3800. doi: 10.1038/s41467-019-11716-6.
E-cadherin (CDH1) is a master regulator of epithelial cell adherence junctions and a well-established tumor suppressor in Invasive Lobular Carcinoma (ILC). Intriguingly, somatic inactivation of E-cadherin alone in mouse mammary epithelial cells (MMECs) is insufficient to induce tumor formation. Here we show that E-cadherin loss induces extrusion of luminal MMECs to the basal lamina. Remarkably, E-cadherin-deficient MMECs can breach the basal lamina but do not disseminate into the surrounding fat pad. Basal lamina components laminin and collagen IV supported adhesion and survival of E-cadherin-deficient MMECs while collagen I, the principle component of the mammary stromal micro-environment did not. We uncovered that relaxation of actomyosin contractility mediates adhesion and survival of E-cadherin-deficient MMECs on collagen I, thereby allowing ILC development. Together, these findings unmask the direct consequences of E-cadherin inactivation in the mammary gland and identify aberrant actomyosin contractility as a critical barrier to ILC formation.
E-钙黏蛋白（CDH1）是上皮细胞黏附连接的主要调节因子，也是浸润性小叶癌（ILC）中成熟的肿瘤抑制因子。有趣的是，单独使小鼠乳腺上皮细胞（MMECs）中的 E-钙黏蛋白失活不足以诱导肿瘤形成。在这里，我们发现 E-钙黏蛋白的缺失会诱导腔 MMECs 挤出到基底膜。值得注意的是，E-钙黏蛋白缺失的 MMECs 可以穿透基底膜，但不会扩散到周围的脂肪垫中。基底膜成分层粘连蛋白和胶原 IV 支持 E-钙黏蛋白缺失的 MMECs 的黏附和存活，而作为乳腺基质微环境主要成分的胶原 I 则不行。我们发现肌动球蛋白收缩的弛豫调节 E-钙黏蛋白缺失的 MMECs 在胶原 I 上的黏附和存活，从而允许 ILC 发展。总之，这些发现揭示了 E-钙黏蛋白在乳腺中的失活的直接后果，并确定了异常的肌动球蛋白收缩性是 ILC 形成的关键障碍。
