Invited Talk

Tissue Fluidification Promotes a Pro-Inflammatory Transcriptional Response in Invasive Breast Carcinoma

Milan University, Department of Medical Biotechnology and Translational Medicine, Via Vanvitelli 32, 20133 Milano, Italy

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The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state that occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. We show that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. Cells react to these protracted mechanical stresses by mounting a mechano-protective response that includes enlarged nuclear size and rigidity, altered heterochromatin distribution, and the remodeling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS/STING-dependent cytosolic DNA response gene program. This mechanically-driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemo- resistance in invasive breast carcinoma.