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McGrail and colleagues report that high intratumoral bacteria abundance is associated with an immunosuppressive microenvironment and resistance to immune checkpoint blockade in head and neck squamous cell carcinoma.

The impact of phage predation on spreading antimicrobial resistance is unclear in the context of its effects on microbial community spatial organization. Here, the authors show that phage predation can promote the spread of plasmid-encoded antibiotic resistance by increasing microbial spatial intermixing.

Break-induced replication (BIR) repairs broken DNA but can also destabilize genomes. The authors identify 33 new genes controlling BIR completion, showing that spindle assembly and spindle positioning checkpoints coordinate repair, and that nuclear pore proteins regulate BIR at multiple steps.

In an arm of an ongoing multicenter phase 2 trial testing different therapies in patients with genetically profiled grade 2 or 3 meningiomas, treatment with an oral CDK4/6 inhibitor met the primary endpoint for progression-free survival at 6 months in patients with CDK or NF2 alterations.

Melanoma cells lacking SOX10 are tolerant to MAPK inhibition (MAPKi) due to elevated TAZ-driven TEAD signaling. Here, the authors develop two inhibitors of TEAD, capable of resensitising SOX10 knockout melanoma cells to MAPKi and offering a strategy to overcome drug tolerance and improve treatment response.

Hu et al. describe how histone H1.0 regulates myofibroblast activation, linking force generation to nuclear organization and gene transcription.

The gut microbiota-derived metabolite indole-3-propionic acid (IPA) is found to enhance mitochondrial fatty acid and amino acid oxidation in CD4⁺ T cells. In mice, IPA-mediated metabolic reprogramming of CD4⁺ T cells exerts anti-inflammatory effects and protects against colitis.

This preclinical study demonstrates the potential of a drug repurposing strategy using the coadministration of tamsulosin, metoprolol, and bromocriptine to provide a mutation-agnostic therapy for inherited retinal degeneration.

Activated hepatic stellate cells of putative mesodermal origin orchestrate scarring during injury. Here, the authors define a discrete morphologically plastic lineage of embryonic mesothelial-derived scar-orchestrating cells, through a distinct quiescent adult precursor, defined and paradoxically inhibited by WT1.

A recombinant antivenom composed of eight nanobodies provides broad protection against venom-induced lethality and dermonecrosis in mice challenged with venoms from cobras, mambas and rinkhals snakes.

Adjuvants are an important component of modern vaccines. Here, the authors employ a phenotypic screen of ~200k compounds and identify PVP-057, a TLR3 agonist with a simple scalable 3-step synthesis, as an adjuvant that induces durable humoral and cellular immunity to varicella-zoster virus (VZV) gE in mice.

A new inhibitor targeting the mitochondrial complex I shows antitumor activity in preclinical models of acute myeloid leukemia and glioblastoma relying on oxidative phosphorylation.

Using differences among strains as a model for inter-individual variation, this paper identifies a conserved metabolicadaptation in C. elegans that compensates for genetic variation.

Hildreth et al. show that during diet-induced obesity, conventional type 1 dendritic cells (cDC1s) in white adipose tissue (WAT) take up DNA-containing apoptotic bodies from adipocytes, which triggers STING-dependent interleukin-12 production from cDC1s, contributing to WAT inflammation in mice.

A 50 microRNA-based dynamic risk score for stratifying individuals with and without type 1 diabetes was developed using samples obtained from multicenter and multiethnic cohorts.

Precisely tuning the genetic response to environmental stimuli is a key step in engineering synthetic biology systems. Here, the authors profile 8269 IPTG-induced promoters to deconstruct the relationship between sequence architecture and gene expression.

APC is a well-known tumour suppressor that is frequently inactivated in colorectal cancer. Here, the authors sequence more than 1000 cancer genes in 468 colorectal cancers and show that mutation signatures can be used to classify the tumours and that multiple mutations in APCare associated with a poor prognosis.

CD40 is typically understood as a costimulatory molecule. Here, the authors show CD4⁺ T cell-induced CD40 signaling in conventional type 1 dendritic cells results in complicated gene expression that can enhance CD8⁺ T cell priming by various underappreciated and independent mechanisms.

O’Sullivan and colleagues identify that the transcription factor Fli1 plays important roles in controlling the establishment of NK cell memory.

Single-nucleus and single-cell RNA sequencing plus spatial profiling with four methods of core biopsies from 60 patients with metastatic breast cancer reveal patient-specific gene expression programs of breast cancer metastases that are maintained across time, site of metastasis and spatial profiling method, with spatial phenotypes correlating with microenvironmental features.

Genomic profiling of tumours can help tailer treatments to the patient, however, it often fails to accurately predict therapeutic outcomes. Here, the authors combine molecular and functional characterisation via BH3 profiling to identify therapeutically targetable vulnerabilities in glioma.

Waves are ubiquitous in nature and occur across various scales and settings. In this Primer, Jafarzadeh et al. discuss techniques for preprocessing and analysing waves, including information on choosing the appropriate methods based on wave properties, and present worked examples using synthetic datasets.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Synthetic methylotrophic organisms provide potential for valorization of greenhouse gas-derived methanol. Here an Escherichia coli strain is generated that reaches a similar growth rate on methanol to many natural methylotrophs and is capable of producing chemicals from this carbon source.

STING is a promising drug target, but selective activation is necessary for safety and efficacy. Researchers have developed a two-component prodrug system for potent pharmacological activation of STING that offers excellent tumour targeting.

The authors present SVclone, a computational method for inferring the cancer cell fraction of structural variants from whole-genome sequencing data.

Choby et al. show that dynamic increases in the copy number of preexisting β-lactamase genes in heteroresistance enables resistance of continua of cellular subpopulations, flexibly overcoming enhanced β-lactams without new evolution and threatening the β-lactam pipeline.

Accurate cell-type identification is vital for single-cell analysis. Here, the authors develop a computational pipeline called “LungMAP CellRef” for efficient, automated cell-type annotation of normal and disease human and mouse lung single-cell datasets.

Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.

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.

Excitatory spiny stellate neurons in the somatosensory cortex are shaped by innervating thalamic inputs and unique expression of genes. Here, the authors show that these neurons play a crucial role in processing distinct whisker signals and forming specialized circuits for sensory perception.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

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.

Whole-genome sequencing data for 2,778 cancer samples from 2,658 unique donors across 38 cancer types is used to reconstruct the evolutionary history of cancer, revealing that driver mutations can precede diagnosis by several years to decades.

The characterization of 4,645 whole-genome and 19,184 exome sequences, covering most types of cancer, identifies 81 single-base substitution, doublet-base substitution and small-insertion-and-deletion mutational signatures, providing a systematic overview of the mutational processes that contribute to cancer development.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Here the authors show in female mice at mid-life that deletion of estrogen receptor β in astrocytes induced cognitive impairment, hippocampal atrophy, glial activation and synaptic loss. ERβ ligand treatment restored cognition and decreased neuropathology in these animals.

Crossing the blood–brain barrier in primates is a major obstacle to gene delivery in the brain. Here an adeno-associated virus variant (AAV.CAP-Mac) is identified and demonstrated for crossing the blood–brain barrier and delivering gene sequences to the brain of different non-human primates species.

There’s an emerging body of evidence to show how biological sex impacts cancer incidence, treatment and underlying biology. Here, using a large pan-cancer dataset, the authors further highlight how sex differences shape the cancer genome.

In somatic cells the mechanisms maintaining the chromosome ends are normally inactivated; however, cancer cells can re-activate these pathways to support continuous growth. Here, the authors characterize the telomeric landscapes across tumour types and identify genomic alterations associated with different telomere maintenance mechanisms.

With the generation of large pan-cancer whole-exome and whole-genome sequencing projects, a question remains about how comparable these datasets are. Here, using The Cancer Genome Atlas samples analysed as part of the Pan-Cancer Analysis of Whole Genomes project, the authors explore the concordance of mutations called by whole exome sequencing and whole genome sequencing techniques.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.