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Proteins can localize to multiple cellular compartments and some exhibit distinct functions depending on their location. This Review discusses the mechanisms of protein localization, the control of specialized protein functions through subcellular localization, and how mislocalization is involved in cancer, neurodegeneration and autoimmunity.

The early genetic evolution of uveal melanoma (UM) remains poorly understood. Here, the authors perform genetic profiling of 1140 primary UMs, including 131 small early-stage tumours, finding that most genetic driver aberrations have occurred by the time small tumours are biopsied; in addition, the15-gene expression profile discriminant score can predict the transition from low- to high-risk tumours.

Here, the authors conduct a metagenomic-based study of England’s rivers to show that biofilm bacteria are taxonomically and functionally diverse and are key to biogeochemical cycling, highlighting the importance of river biofilm bacteria in understanding and monitoring freshwater ecosystem health.

MYC-driven medulloblastoma is highly aggressive and associated with poor survival. Here, the authors perform single nuclei multi-omic analysis of matched primary and recurrent tumours and identify potential resistance mechanisms and targetable pathways.

GATA2 deficiency is one of the major causes of hereditary pediatric myelodysplastic neoplasms (MDS). Using iPSC-based models, this work recapitulates stepwise mutational trajectories in GATA2-related MDS and reveals their impact on myeloid differentiation.

Bright electron bunches power particle physics and photon science. Here, reproducible bunches were generated in a plasma with simultaneous high charge per unit energy and low emittance, advancing a scheme to produce ultra-bright bunches in future.

Analysis of cancer genome sequencing data has enabled the discovery of driver mutations. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium the authors present DriverPower, a software package that identifies coding and non-coding driver mutations within cancer whole genomes via consideration of mutational burden and functional impact evidence.

Al-Hilal, Chrysovergi et al. identify a role for durotaxis in lung fibrosis and metastatic pancreatic cancer, mediated by the FAK–paxillin mechanosensor complex, and demonstrate therapeutic targeting of this pathway using the small molecule JP-153.

Imidazole propionate produced by gut microbiota is associated with atherosclerosis in mouse models and in humans, and causes the development of atherosclerosis through activation of the imidazoline-1 receptor in myeloid cells.

Missense mutations in the twelfth codon of KRAS are key drivers of lung cancer. Here, the authors develop a CRISPR-High Fidelity-Cas9-based strategy to target KRAS-G12C and KRAS-G12D mutants, reducing tumourigenicity without wild type KRAS off-targeting and circumventing certain therapy resistance mechanisms in preclinical models.

This study shows that mithramycin suppresses the EWS::FLI1 transcription factor in Ewing sarcoma using a hybrid CUT, Tag & GRO assay, revealing mechanism, need for continuous dosing, and supporting clinical use of next-gen analog AIT-102.

Axonal injury, induced in the white matter by expansion of early tumour cells, is a key driver of glioblastoma progression.

Su et al. report that the super-enhancer K5aSE orchestrates Klf5andadditional targets via 3D chromatin interactions in ES cells, with CTCF-mediated chromatin domains maintaining this regulatory network essential for ES cell identity.

Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Patients with myelodysplastic syndromes (MDS) have limited therapeutic options. Here the authors show that functionally impaired NK cells contribute to immune escape of pre-malignant clones in early stage MDS and that NK adoptive cell therapy can be considered to prevent or delay the development of MDS.

MASH is driven by the secreted GPNMB ectodomain, which binds hepatocyte RYK to activate ERK1/2 and promote lipid uptake and lipogenic programs; blocking the GPNMB–RYK axis prevented and treated MASH in preclinical models.

Single-cell data analysis is challenging due to inherent noise and sparsity. Here, authors introduce scMINER, a mutual information-based integrative tool to enhance clustering and reveal regulatory networks and hidden biological drivers by transforming scRNA-seq expression into activity profiles.

Analysis of medulloblastomas in humans and mice shows that the functional consequences of ZIC1 mutations are exquisitely dependent on the cells of origin that give rise to different subgroups of medulloblastoma.

Most driver models were designed for specific scenario. Here, the authors developed a driver behaviour model that can be applied to multiple scenarios and show that human-like driving behaviour emerges when the Driver’s Risk Field is coupled to a controller that maintains the perceived risk below a threshold level.

Whole-transcriptome sequencing of a subset of 75 non-small-cell lung cancer specimens in a multi-institutional genome screening study identified a fusion of the CLIP1 and LTK genes with transformational potential due to constitutive LTK kinase activity.

This study identifies GCN5, a histone acetyltransferase, as a driver of metabolic dysfunction-associated steatotic liver disease progression via LXRα/SREBP1c-mediated lipogenesis, and demonstrates that pharmacological inhibition of GCN5 alleviates disease in a study with male mice.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

Olweus and colleagues identify a T cell receptor reactive against the recurrent D835Y driver mutation in FLT3 in acute myeloid leukemia and show that engineered T cells against this neoantigen provide efficient immunotherapy.

We show the evolution of a case of EGFR mutant lung cancer treated with a combination of erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine targeting somatic mutations, including EGFR exon 19 deletion.

Sebaceous tumours are a rare skin tumour which have highly variable outcomes. Here, the authors analyse tumours from 222 patients to identify genomic mutations to assess the molecular portrait of the spectrum of tumours.

It’s challenging to capture “hidden” drivers that may not be genetically-altered or differentially-expressed from omics data. Here the authors developed NetBID2, a comprehensive network-based toolbox with versatile features, enabling the integration of multi-omics data to expose such hidden drivers.

How microglia regulate adult hippocampal neurogenesis and cognitive and affective behavior remains poorly understood. Here, the authors show that TGF-β-deficient microglia increase adult neurogenesis in the subgranular zone and alter anxiety-like behavior in mice.

Analysis of pan-cancer clinical genomic sequencing finds that body mass index associates with driver mutations in certain cancer types, including most prominently lung adenocarcinoma. Obesity may thus influence tumor genetics.

Lung adenocarcinomas bearing the ID2 mutational signature display increased LINE-1 retrotransposon activity, which contributes to their fast evolutionary dynamics and aggressive phenotype.

A mathematical framework to estimate the fitness of cancer driver mutations by integrating mutational bias, oncogenicity and immunogenicity finds fundamental trade-offs in cancer evolution.

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

It is currently unclear if cell-free DNA samples from metastatic cancers are as informative as tissue ones for cancer profiling. Here the authors show that cell-free DNA samples from rapid autopsies capture clonal and subclonal alterations of metastatic tumours and reveal more driver alterations than single tissue samples.

By integrating DNA genotype and RNA sequencing data from human samples, d’Escamard et al. identify a gene regulatory co-expression supernetwork that plays an important role in fibromuscular dysplasia, a poorly understood disease affecting 3–5% of adult females.

This study uses single-cell DNA sequencing to analyze genomic evolution in pancreatic cancer using a cohort of multiregionally and longitudinally sampled patients’ tissues across various clinical contexts.

Wolfram syndrome, caused by WFS1 or CISD2 gene mutations, disrupts ER Ca²⁺ regulation in neurons. Here, the authors show how these mutations impair ER-mitochondria interactions, compromise Ca²⁺ transfer and mitochondrial function, and lead to bioenergetic deficits and oxidative stress.

Spiradenoma and cylindroma are skin adnexal tumors that can behave aggressively and undergo malignant transformation. Here, the authors genetically assess a cohort of these adnexal tumours, highlighting recurrent ALPK1 mutations and revealing the genomic landscape of these rare tumours.

It is difficult to identify cancer driver genes in cancers, for instance BRCA1 mutated breast cancer, that are characterised by large scale genomic alterations. Here, the authors develop genetically engineered mouse models of BRCA1-deficient breast cancer that allow highthroughput in vivo perturbation of candidate driver genes, validating drivers Myc, Met, Pten and Rb1, and identifying MCL1 as a collaborating driver whose targeting can impact efficacy of PARP inhibition.

Diffuse Intrinsic Pontine Gliomas are diagnosed by sampling a small portion of the tumour. Here, using multiple samples from tumours, the authors analyse the spatial and temporal distribution of driver mutations revealing that H3K27M mutations arise first in tumorigenesis followed by a specific invariable sequence of driver mutations, which are homogeneously distributed across the tumour mass.

The accumulation of genetic and epigenetic mutations in cancer cells can drive malignant growth. Here, the authors model the evolution of intratumoral diversity and examine the classification of driver and passenger mutations, heterogeneity within tumours, and the dynamics of tumour response to targeted therapies.

In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.

This study uses somatic mutations as a natural barcoding system to retrospectively and prospectively trace the fate of hematopoietic stem cells across all major blood cell lineages in healthy aged individuals. It reveals the existence of intrinsically fate-biased hematopoietic stem cells in native human hematopoiesis, validated by transplantation assays.

Cerebral organoids can be used to gain insights into neuropsychiatric disorders. Here the authors carry out RNAseq characterization from organoids derived from donors with autism spectrum disorder to identify associated cell type specific driver genes.

Using single-nucleus and spatial transcriptomics, the authors reveal resilience signatures in neocortical layer 4 neurons. They show KCNIP4 protects these cells by reducing hyperexcitability, a driver of neurodegeneration.