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The high-plasticity cell state (HPCS) is a critical hub that enables reciprocal transitions between cancer cell states, and targeting the HPCS may suppress cancer progression and eradicate treatment resistance.

González-Gualda, Reinius et al. demonstrate that platinum-based chemotherapy-induced senescence promotes malignancy in ovarian and lung cancer via TGFβ ligands, with evidence in mouse models validated in clinical samples. Concomitantly blocking TGFβ signaling with chemotherapy reduces tumor burden and increases survival in mice.

A forward genetic screen in Caenorhabditis elegans reveals that decreased levels of the ferredoxin FDX2 suppress the loss of frataxin in worms and in mice by relief of FDX2 inhibition of frataxin-stimulated NFS1 activity.

How do bacteria control formate flow, essential for microbial life? Researchers detected specialized molecular checkpoints that fine-tune small-molecule transport by combining cryo-electron microscopy with in silico, in vitro and in vivo approaches.

The cell states and lineage connections underlying the progression from Barrett’s esophagus to esophageal adenocarcinoma remain unresolved. Here, the authors use single-cell lineage tracing and transcriptomics to analyse patient samples from the gastroesophageal junction and identify cellular relationships in the progression of Barrett’s esophagus to cancer.

RNA localization is mediated by kinesin motors and anchoring. However, mechanisms underlying specificity are unclear. Here, the authors find that MBNL protein’s zinc fingers prefer specific kinesins, and its unstructured tail mediates membrane anchoring.

Neural crest cells have been implicated in heart development, yet the mechanisms by which they act have remained elusive. Here, the authors show neural crest cells modulate Wnt signalling in cardiac progenitors, providing new insight into the mechanisms underpinning congenital heart defects.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

In the adrenal cortex, cholesterol used for steroid production is stored in lipid droplets. The authors demonstrate here the importance of the transcription factor HHEX in maintaining glucocorticoid levels and protecting lipid droplets from androgen-induced lipid depletion.

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.

In this Review, Rowles and Patti present metabolomics workflows to study cancer across scales. They explore the nutrient demands of cancer cells and how those needs can be fulfilled through metabolic interactions within the tumour microenvironment or systemic crosstalk with distant tissues, and discuss the opportunities and challenges of each approach and offer insights into future research directions.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.

Here, the authors report that combining Army Liposome Formulation with QS21 saponin (ALFQ) and Alum to formulate the ΔV1gp120 boost decreases the risk of simian immunodeficiency virus (SIV) mac251 acquisition in female macaques.

3.4-million-year-old hominin fossils discovered in Ethiopia provide insight into the diet and locomotion of Australopithecus deyiremeda.

The molecular mechanisms of cell entry for the recently identified highly pathogenic feline coronavirus FCoV-23 are characterized in detail.

Here the authors describe the discovery of a class of small molecule splicing modifiers which are orally bioavailable, cross the blood-brain barrier, and lower levels of huntingtin in a mouse model of Huntington’s disease (HD).

In thromboinflammation, early tissue plasminogen activator administration directly improves endothelial barrier function, prophylactic defibrotide and enoxaparin suppress microvascular thromboinflammation through endothelium-mediated mechanisms and combining enoxaparin with crizanlizumab reduces microvascular occlusion and protects endothelial function in sickle cell disease.

Kalia et al. investigate metabolic changes in Alzheimer’s disease (AD) using blood metabolomics, and show that lysophosphatidylcholines are associated with early amyloidosis in AD as measured by P-tau181 and P-tau217.

Aneuploidy, abnormal chromosome number, is a major cause of early pregnancy loss. Here the authors determine the extent of post-implantation development of human embryos with common aneuploidies in culture, finding developmental arrest of monosomy 21 embryos, and trophoblast hypo-proliferation in trisomy 16 embryos.

In lung adenocarcinoma, antibodies against endogenous retroviruses promote anti-tumour activity, and expression of endogenous retroviruses can predict outcomes of immunotherapy.

Ovarian and endometrial cancers with CCNE1-amplification are often resistant to standard treatment. Here, the authors identify that CCNE1-amplified gynecological cancer is sensitive to combined PKMYT1 and ATR inhibition via CDK1 activation, resulting in premature mitosis, DNA damage, cell apoptosis and reduced tumour growth and metastasis.

Multi-omics datasets pose major challenges to data interpretation and hypothesis generation owing to their high-dimensional molecular profiles. Here, the authors develop ActivePathways method, which uses data fusion techniques for integrative pathway analysis of multi-omics data and candidate gene discovery.

Integration of snATAC-seq and snRNA-seq data from brains of individuals with major depressive disorder identifies chromatin accessibility alterations and functional enrichment of risk variants in deep-layer excitatory neurons. Gray matter microglia in these individuals show decreased accessibility at sites bound by regulators of immune homeostasis.

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.

The migration of T cells into tumours and how this is regulated by metabolic pathways is not completely understood. Here the authors use human and xenograft mouse models to explore the functional changes in T cells during migration in tumours and how glycolytic and TCA cycle metabolism is involved.

Zhang, Ma et al. report that ROS-activated O-GlcNAc transferase promotes FOXK2 O-GlcNAcylation and nuclear translocation to upregulate SLC7A11 expression, thereby modulating ferroptosis sensitivity, tumour development and chemoradiotherapy efficacy.

This study demonstrates that the MKK3b/6 signalling pathway drives the skeletal muscle growth-promoting effects of resistance exercise.

In this study, the authors report the CoVerage tool (www.sarscoverage.org) for viral genomic surveillance and show that it predicted SARS-CoV-2 Variants of Concern, of Interest and under Monitoring together with their antigenic and evolutionary alterations almost three months prior to their WHO designation.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

Lipoprotein uptake dependent on sulfated glycosaminoglycans linked to cell-surface proteoglycans is a key determinant of ferroptosis sensitivity in cancer.

Genetic and functional studies implicate allele-specific regulation of OAS1 splicing and nonsense-mediated decay in COVID-19 severity. The OAS1 risk haplotype is also associated with reduced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1.

Bacterial products in the gut–liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8⁺ T cells with immunomodulatory ability.

Genome-scale CRISPR–Cas9-based synthetic lethality screens identify PKMYT1 as a potential therapeutic target in tumours with CCNE1 amplification.

The presence of CD8⁺ T cells in the cytoplasm of biliary epithelial cells (BEC) has been associated with primary biliary cholangitis. Here, the authors demonstrate that CD8⁺ T cells invade BEC using a mechanism that is dependent on cytoskeletal rearrangements and E-cadherin:β-catenin interactions.

Combined high-throughput protein engineering with machine learning to curate libraries of CRISPR genome-editing enzymes with distinct genome targeting properties is described.

Clonal hematopoiesis is driven by the selective advantage of mutant hematopoietic stem cells. Here, authors discover that elevated mitochondrial activity is a targetable mechanism by which mutant hematopoietic stem cells gain a selective advantage.

Phosphoribosyl pyrophosphate synthetase (PRPS1), an enzyme that regulates de novo nucleotide synthesis, was found to be O-GlcNAcylated, which increases PRPS1 activity, and is associated with increased tumorigenesis and resistance to chemoradiotherapy.

Thomas, Egan et al. report that hexokinase 2 localizes to the nucleus of leukaemic and normal haematopoietic cells to maintain stemness by interacting with nuclear proteins and modulating chromatin accessibility independently of its kinase activity.

Roles of of viruses in ocean subsurface oxygen maxima are unclear. Here, the authors analyse Bermuda Atlantic Time Series data to show that viruses may drive SOM in stratified oceans by boosting nutrient recycling and phytoplankton productivity linking virus activity to oxygen buildup and a stronger microbial loop.

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.

Parkinson’s disease (PD) involves toxic protein buildup and energy failure in neurons. Continuously breathing low-oxygen air protected mice from PD-like neuronal loss and reversed symptoms, even after they began, suggesting that hypoxia may protect neurons.

The transcription factor CREM is a pivotal regulator of NK cell function, making CREM a valuable target to increase the efficacy of anticancer immunotherapies based on this cell population and chimeric antigen receptors.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

Liver fibrosis develops from excessive matrix produced by activated hepatic stellate cells (HSCs). Here, authors identify ABHD17B via an siRNA screen and show that ABHD17B regulates the fibrotic activity of HSCs and promotes liver fibrosis in vivo.

Protein-mediated transport is implicated in trafficking fatty acids at contact sites of lipid droplets and mitochondria. Here, the authors use proteomics to catalogue the proteins at this contact site and report a mechanism of fatty acid transfer that regulates fatty acid oxidation and lipid homeostasis.