The authors report a link between mitosis, the formation of micronuclei and DNA-damage-induced cGAS-dependent inflammation. Ionizing radiation and genotoxic cancer therapy induce innate immunity mechanisms and lead to an increased production of inflammatory cytokines. The delayed nature of this response, which occurs a few days after treatment, is not well understood. Roger Greenberg and colleagues report a link between mitosis, the formation of micronuclei and DNA-damage-induced inflammatory signalling involving the pattern recognition receptor cGAS in cancer cells. The authors advise that temporal modulation of the cell cycle is important to consider in therapeutic approaches involving genotoxic agents and immune checkpoint blockers. Elsewhere in this issue, Andrew Jackson and colleagues provide evidence for an underlying mechanism whereby ruptured micronuclei activate a cell-autonomous inflammatory response via cGAS. Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumour microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumour responses to radiotherapy1. A poorly understood feature of these responses is the delayed onset (days), in contrast to the acute DNA-damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate-limiting steps that are essential for DNA-damage-induced inflammation. Here we show that cell cycle progression through mitosis following double-stranded DNA breaks leads to the formation of micronuclei, which precede activation of inflammatory signalling and are a repository for the pattern-recognition receptor cyclic GMP–AMP synthase (cGAS). Inhibiting progression through mitosis or loss of pattern recognition by stimulator of interferon genes (STING)–cGAS impaired interferon signalling. Moreover, STING loss prevented the regression of abscopal tumours in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.

Cell migration through solid tissue often involves large contortions of the nucleus, but biological significance is largely unclear. The nucleoskeletal protein lamin-A varies both within and between cell types and was shown here to contribute to cell sorting and survival in migration through constraining micropores. Lamin-A proved rate-limiting in 3D migration of diverse human cells that ranged from glioma and adenocarcinoma lines to primary mesenchymal stem cells (MSCs). Stoichiometry of A- to B-type lamins established an activation barrier, with high lamin-A:B producing extruded nuclear shapes after migration. Because the juxtaposed A and B polymer assemblies respectively conferred viscous and elastic stiffness to the nucleus, subpopulations with different A:B levels sorted in 3D migration. However, net migration was also biphasic in lamin-A, as wild-type lamin-A levels protected against stress-induced death, whereas deep knockdown caused broad defects in stress resistance. In vivo xenografts proved consistent with A:B-based cell sorting, and intermediate A:B-enhanced tumor growth. Lamins thus impede 3D migration but also promote survival against migration-induced stresses.

The nucleus is linked mechanically to the extracellular matrix via multiple polymers that transmit forces to the nuclear envelope and into the nuclear interior. Here, we review some of the emerging mechanisms of nuclear mechanosensing, which range from changes in protein conformation and transcription factor localization to chromosome reorganization and membrane dilation up to rupture. Nuclear mechanosensing encompasses biophysically complex pathways that often converge on the main structural proteins of the nucleus, the lamins. We also perform meta-analyses of public transcriptomics and proteomics data, which indicate that some of the mechanosensing pathways relaying signals from the collagen matrix to the nucleus apply to a broad range of species, tissues, and diseases.