aPKCi triggers basal extrusion of luminal mammary epithelial cells by tuning contractility and vinculin localization at cell junctions

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 48; pp. 24108 - 24114
• Main Authors: Villeneuve, Clémentine, Lagoutte, Emilie, de Plater, Ludmilla, Mathieu, Samuel, Manneville, Jean-Baptiste, Maître, Jean-Léon, Chavrier, Philippe, Rossé, Carine
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.11.2019
• Series: PNAS Plus
• Subjects: Biological Sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Adhesion; Cell adhesion & migration; Cell junctions; Cell Line, Tumor; Cell Separation; Contractility; Epithelial cells; Epithelium; Extrusion; Humans; Intercellular Junctions - metabolism; Isoenzymes - genetics; Isoenzymes - metabolism; Isoenzymes - physiology; Kinases; Life Sciences; Localization; Mammary gland; Metastases; Neoplasm Invasiveness; PNAS Plus; Protein kinase C; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Kinase C - physiology; Proteins; Regulators; Vinculin; Vinculin - metabolism; cell junction; cell segregation; vinculin; cell extrusion; atypical PKC ι
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1906779116

Metastasis is the main cause of cancer-related deaths. How a single oncogenic cell evolves within highly organized epithelium is still unknown. Here, we found that the overexpression of the protein kinase atypical protein kinase C ι (aPKCi), an oncogene, triggers basally oriented epithelial cell extrusion in vivo as a potential mechanism for early breast tumor cell invasion. We found that cell segregation is the first step required for basal extrusion of luminal cells and identify aPKCi and vinculin as regulators of cell segregation. We propose that asymmetric vinculin levels at the junction between normal and aPKCi⁺ cells trigger an increase in tension at these cell junctions. Moreover, we show that aPKCi⁺ cells acquire promigratory features, including increased vinculin levels and vinculin dynamics at the cell–substratum contacts. Overall, this study shows that a balance between cell contractility and cell–cell adhesion is crucial for promoting basally oriented cell extrusion, a mechanism for early breast cancer cell invasion.