Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion

• Published in: Cell 2021-09, Vol.184 (20), p.5230-5246.e22
• Main Authors: Nader, Guilherme Pedreira de Freitas, Agüera-Gonzalez, Sonia, Routet, Fiona, Gratia, Matthieu, Maurin, Mathieu, Cancila, Valeria, Cadart, Clotilde, Palamidessi, Andrea, Ramos, Rodrigo Nalio, San Roman, Mabel, Gentili, Matteo, Yamada, Ayako, Williart, Alice, Lodillinsky, Catalina, Lagoutte, Emilie, Villard, Catherine, Viovy, Jean-Louis, Tripodo, Claudio, Galon, Jérôme, Scita, Giorgio, Manel, Nicolas, Chavrier, Philippe, Piel, Matthieu
• Format: Article
• Language: English
• Subjects: Animals; Breast Neoplasms - enzymology; Breast Neoplasms - pathology; Cell Line; Cellular Senescence; Collagen - metabolism; Disease Progression; DNA Damage; Exodeoxyribonucleases - metabolism; Female; Humans; Life Sciences; Mice; Neoplasm Invasiveness; Nuclear Envelope - metabolism; Nuclear Envelope - ultrastructure; Phosphoproteins - metabolism; Proteolysis; TREX1, nuclear envelope rupture, DNA damage, mammary duct carcinoma, tumor invasion, senescence, breast cancer, cGAS, confinement, epithelial to mesenchymal transition; Xenograft Model Antitumor Assays
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.08.035

Although mutations leading to a compromised nuclear envelope cause diseases such as muscular dystrophies or accelerated aging, the consequences of mechanically induced nuclear envelope ruptures are less known. Here, we show that nuclear envelope ruptures induce DNA damage that promotes senescence in non-transformed cells and induces an invasive phenotype in human breast cancer cells. We find that the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. We propose that DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells. [Display omitted] •Deformed nuclei and DNA damage are enriched at micro-invasive foci of breast cancer•TREX1 causes DNA damage in deformed nuclei upon nuclear envelope rupture events•TREX1 drives senescence in normal cells and an invasive phenotype in cancer cells•Nuclear envelope rupture events and DNA damage are observed in human tumors Extreme nuclear deformations in dense microenvironments lead to repeated nuclear envelope rupture followed by TREX1-dependent chronic DNA damage. This triggers a partial EMT in malignant cells which might underlie tumor progression.