Federico Giorgia, Carotenuto Angelo Rosario, Cutolo Arsenio, Palumbo Stefania, Moccia Marialuisa, Paladino Simona, Santoro Massimo, Russo Tommaso, Fraldi Massimiliano, Carlomagno Francesca
Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", Napoli, Italy.
Department of Structures for Engineering and Architecture, University of Naples "Federico II", Napoli, Italy.
Sci Rep. 2025 May 23;15(1):18037. doi: 10.1038/s41598-025-03317-9.
Neoplastic transformation is accompanied by critical changes in cell mechanical properties, including reduced cell elasticity. By leveraging such mechanical flaw, exposure to low intensity therapeutic ultrasounds (LITUS) has been proposed as a tool for selective killing of cancer cells. Here, we have developed dynamic models to address the morpho-mechanical differences between prostate cancer and non-tumoral counterparts and studied the effects of LITUS on cell viability. We show that LITUS exposure (1 MHz) leads to cancer-selective cytoskeletal disruption associated to loss of nuclear envelope integrity, DNA damage marked by γH2AX and 53BP1 foci, and release of DNA into the cytosol with activation of the cGAS-STING signaling cascade. Mechanistically, the LINC complex, which connects the cytoskeleton to nucleoskeleton and chromosomes, is critical to mediate nuclear rupture triggered by LITUS. Accordingly, genetic ablation of the LINC component SUN2 tuned down DNA damage and cGAS-STING signaling while the inactivation of the endosomal sorting complex (ESCRT), required for the transport machinery that preserves the nuclear envelope integrity, enhanced cell killing by LITUS. In conclusion, LITUS induce cancer cell DNA damage and an innate immune response, this suggesting LITUS treatment as a mechanobiology-driven anti-neoplastic strategy.
肿瘤转化伴随着细胞力学特性的关键变化，包括细胞弹性降低。通过利用这种力学缺陷，低强度治疗性超声（LITUS）已被提议作为一种选择性杀死癌细胞的工具。在此，我们开发了动态模型来解决前列腺癌与非肿瘤对应物之间的形态力学差异，并研究了LITUS对细胞活力的影响。我们表明，LITUS暴露（1MHz）会导致癌症选择性的细胞骨架破坏，这与核膜完整性丧失、以γH2AX和53BP1病灶为标志的DNA损伤以及DNA释放到细胞质中并激活cGAS-STING信号级联反应有关。从机制上讲，连接细胞骨架与核骨架和染色体的LINC复合体对于介导LITUS触发的核破裂至关重要。因此，LINC成分SUN2的基因消融降低了DNA损伤和cGAS-STING信号，而内体分选复合体（ESCRT）的失活增强了LITUS对细胞的杀伤作用，ESCRT是维持核膜完整性的转运机制所必需的。总之，LITUS诱导癌细胞DNA损伤和先天免疫反应，这表明LITUS治疗是一种机械生物学驱动的抗肿瘤策略。
