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

• DOI: 10.1016/j.cell.2021.08.035
• Publication Date: 2021-09-21T14:38:30Z
• Authors: Guilherme Pedreir...; Sonia Agüera-Gonz...; Fiona Routet; Matthieu Gratia; Mathieu Maurin; Valeria Cancila; Clotilde Cadart; Andrea Palamidessi; Rodrigo Nalio Ramos; Mabel San Roman; Matteo Gentili; Ayako Yamada; Alice Williart; Catalina Lodillinsky; Emilie Lagoutte; Catherine Villard; Jean-Louis Viovy; Claudio Tripodo; Jérôme Galon; Giorgio Scita; Nicolas Manel; Philippe Chavrier; Matthieu Piel
• Keywords: 0301 basic medicine; senescence; TREX1; Nuclear Envelope; CONFINEMENT; Breast Neoplasms; Settore MED/08 - Anatomia Patologica; DNA DAMAGE; EPITHELIAL TO MESENCHYMAL TRANSITION; Cell Line; nuclear envelope rupture; Mice; 03 medical and health sciences; breast cancer; BREAST CANCER; https://purl.org/becyt/ford/3.1; Settore MED/05 - Patologia Clinica; Animals; Humans; Neoplasm Invasiveness; https://purl.org/becyt/ford/3; NUCLEAR ENVELOPE RUPTURE; mammary duct carcinoma; Cellular Senescence; epithelial to mesenchymal transition; tumor invasion; Phosphoproteins; Xenograft Model Antitumor Assays; CGAS; Exodeoxyribonucleases; SENESCENCE; confinement; TREX1, nuclear envelope rupture, DNA damage, mammary duct carcinoma, tumor invasion, senescence, breast cancer, cGAS, confinement, epithelial to mesenchymal transition; Animals; Breast Neoplasms; Cell Line; Cellular Senescence; Collagen; Disease Progression; Exodeoxyribonucleases; Female; Humans; Mice; Neoplasm Invasiveness; Nuclear Envelope; Phosphoproteins; Proteolysis; Xenograft Model Antitumor Assays; DNA Damage; Proteolysis; TREX1, nuclear envelope rupture, DNA damage, mammary duct carcinoma, tumor invasion, senescence, breast cancer, cGAS, confinement, epithelial to mesenchymal transition, Animals, Breast Neoplasms, Cell Line, Cellular Senescence, Collagen, Disease Progression, Exodeoxyribonucleases, Female, Humans, Mice, Neoplasm Invasiveness,Nuclear Envelope, Phosphoproteins,Proteolysis, Xenograft Model Antitumor Assays, DNA Damage; Disease Progression; DNA damage; TUMOR INVASION; Female; Collagen; MAMMARY DUCT CARCINOMA; cGAS; DNA Damage

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.