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Chromosomal instability in cancer is linked to endoplasmic reticulum stress signalling, immune suppression and metastasis, which is mediated by the cGAS–STING pathway, suppression of which can reduce metastasis.

Ionizing radiations (IRs) cause widespread genomic damage and can, through unknown mechanisms, lead to changes in chromosome numbers by perturbing the cells undergoing mitosis. Here, the authors investigate the potential mechanism behind the increased susceptibility of mitotic cells to IRs.

The molecular underpinnings driving uveal melanoma (UM) progression are unknown. Here the authors show that loss of Polycomb Repressive Complex 1 triggers chromosomal instability, which promotes inflammatory signaling and migration in UM.

Missegregated chromosomes that are sequestrated in micronuclei are subject to changes in histone modifications leading to abnormalities in chromatin accessibility that remain long after the chromosomes have been reincorporated into the primary nucleus.

A study reveals how chromosomal instability and resultant TP53 loss enhance fatty acid metabolism to drive breast cancer brain metastasis. This metabolic dependency provides new insights into therapeutic vulnerabilities of aneuploid tumors.

A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disrupts immunity.

In chromosomally unstable tumour cells, rupture of micronuclei exposes genomic DNA and activates the cGAS–STING cytosolic DNA-sensing pathway, thereby promoting metastasis.

Single-cell analysis of lung cancer progression uncovers developmental and regenerative programs co-opted by cancer cells and immune-mediated pruning during metastatic outbreak

Lung samples collected soon after death from COVID-19 are used to provide a single-cell atlas of SARS-CoV-2 infection and the ensuing molecular changes.

Locally confined epithelial malignancies undergo a phase transition from a solid-like to liquid-like state, a process called unjamming, where associated chronic intracellular strain causes nuclear envelope rupture, leading to the emergence of pro-metastatic traits due to cGAS–STING pathway activation.

Analyses of in vivo models, cell lines and patient-derived samples show that apolipoprotein B mRNA-editing catalytic subunit 3B (APOBEC3B) not only restrains lung tumor initiation but also that its upregulation is associated with resistance to targeted therapies. This study highlights the complex and context-dependent role of APOBEC3B in lung cancer.

Collisions of transcription and replication machineries on the same DNA strand threaten genomic stability. Here, the authors show that RAD52 prevents these collisions by regulating R-loop formation and resolution. RAD52 deficiency leads to increased R-loops, exacerbated collisions, DNA damage, and higher mutational burden in tumors.

Izar and colleagues demonstrate that loss of Pip4k2c in melanoma cells promotes liver metastatic tropism driven by PI3K-AKT pathway activation in the insulin-rich liver milieu, which can be abrogated by inhibition of SGLT2 or a ketogenic diet.

Mutations arising from APOBEC3-induced cytidine deamination are often found in advanced human cancers, yet how APOBEC3 promotes tumor progression remains poorly understood. A new study finds that APOBEC3A drives chromosomal instability in a deaminase-domain-independent manner, thereby promoting STING-dependent cancer metastasis.

The CIP2A–TOPBP1 complex tethers fragmented chromosomes from micronuclei for asymmetric mitotic inheritance, explaining distinct patterns of chromosome rearrangements in cancers and genomic disorders.

Multi-modal analysis of genomically unstable ovarian tumours characterizes the contribution of anatomical sites and mutational processes to evolutionary phenotypic divergence and immune resistance mechanisms.

Chromosomal instability (CIN) is a dynamic phenotype characterized by changes in chromosome number and structure and is a hallmark of clinically aggressive malignancies. Nonetheless, the ability of cancer cells to tolerate CIN creates several potential therapeutic vulnerabilities. In this Review, the authors describe the development of CIN and how this phenotype promotes carcinogenesis and tumour progression as well as describing the various attempts to develop targeted therapies based on the specific vulnerabilities of these tumours.

Chromosomal instability (CIN) drives cancer progression through diverse mechanisms. The authors review the molecular consequences of CIN in advanced cancer, such as genomic and phenotypic heterogeneity and cancer cell-intrinsic inflammation.

Chromosomal instability enables the continuous selection of somatic copy number alterations, which are established as ordered events that often occur in parallel, throughout tumour evolution and metastasis.

Analysis of genotyping data for more than 150,000 individuals from the UK Biobank using long-range phase information sheds light on mechanisms of clonal haematopoiesis.

Incorrectly oriented chromosomes in mitosis can lead to chromosome instability and aneuploidy. The kinesins Kif2b and MCAK stimulate kinetochore-microtubule dynamics to correct mis-orientations.

By integrating discovery science with clinical practice and therapeutic intervention, clinician-scientists fulfil a unique role in cancer research. However, their numbers are in decline, which is creating the need for flexible training and research opportunities to ensure their future.