Tissue fluidification promotes a cGAS/STING-mediated cytosolic DNA response in invasive breast cancer [RNA-seq of Organoids]. Tissue fluidification promotes a cGAS/STING-mediated cytosolic DNA response in invasive breast cancer [RNA-seq of Organoids]

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 impact phenotypes during carcinoma progression remains unclear. We show, here 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 results in a change in cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemo-resistance in invasive breast carcinoma. Overall design: RNA-seq, 2 conditions (rotating and non-rotating), 5 organoids (3 rotating and 2 non-rotating) derived from 5 patients

局部受限的上皮源性恶性肿瘤逐步进展为浸润性癌的过程，常由解阻塞（unjamming）过程所促进——解阻塞是一种在多种组织中发生的、从固态向液态转变的相变现象。目前尚不明确这种组织水平的力学转变是否会影响癌进展过程中的细胞表型。
我们在此证实，伴随解阻塞过程出现的细胞密度大幅波动，会引发细胞与细胞核反复承受机械形变。细胞会针对这类持续性机械应力启动机械保护应答，具体表现为细胞核体积与刚度增大、异染色质分布改变，以及将核周肌动蛋白结构重塑为肌动蛋白环。与解阻塞相关的慢性牵张与应力，再加上核纤层蛋白B1（Lamin B1）水平降低，最终会引发DNA损伤与核膜破裂，释放胞质DNA并激活依赖cGAS/STING的胞质DNA应答基因程序。这种由机械力驱动的转录重编程最终会导致细胞状态改变，出现恶性特征，包括浸润性乳腺癌中的上皮-间质可塑性表型与化疗耐药性。
整体实验设计：RNA测序（RNA-seq），设置2组处理条件（旋转组与非旋转组），使用源自5名患者的类器官（其中3个为旋转组、2个为非旋转组）。