Research Briefing

We present SpaHDmap, a deep learning framework that integrates histology images with spatial transcriptomic data to derive high-resolution and interpretable spatial metagenes. We demonstrate that SpaHDmap effectively generates fine-grained spatial metagenes, reveals refined spatial structures and enables joint analysis of multiple samples across different experimental conditions.

Our study showed that lineage-determining transcription factors, such as EBF1 in B cell lymphoma and TCF1 in T cell leukaemia, shape 3D genome architecture by constraining cohesin movement. Cohesin in turn positions enhancers at the spatial centres of oncogenic loci and enables multi-enhancer regulation of key oncogenes. Together, these findings identify a unifying mechanism that links transcription factor activity, chromatin topology and oncogene control.

We present CellNavi, a deep learning framework that predicts driver genes that orchestrate cellular transitions by modelling cell states on a biologically meaningful manifold. We demonstrated how CellNavi predictions of driver genes have potential applications in advancing cell therapy, uncovering key factors that drive cellular diseases, and identifying crucial genes involved in drug responses.

Ageing and cancer are often seen as divergent tissue fates. In our study, we identify a protective programme, called senescence-coupled differentiation (or seno-differentiation), that eliminates cancer-prone stem cells by pushing them to differentiate. Whether melanocyte stem cells follow this path or bypass it under carcinogenic stress determines tissue outcomes: hair greying or melanoma development.

Gene fusions are potent drivers of cancer, and nuclear condensates are known to have a role in transcription. By creating synthetic fusion oncogenes, we show that nuclear condensate formation might be a general feature of fusion oncoprotein-directed transcription, including in brain tumour development.

How multiple chaperones are organized to co-ordinate their activities has been unclear. We observed that the chaperone PDIA6 forms phase-separated condensates in the endoplasmic reticulum to which several additional chaperones are recruited. These multi-chaperone condensates constitute a dedicated endoplasmic reticulum sub-compartment that facilitates protein biogenesis and prevents protein misfolding and aggregation.

Dietary nutrients are key regulators of antitumour immune responses. Our study reveals that galactose, a sugar commonly found in the diet, reprograms hepatocytes to prevent T cell exhaustion and enhance antitumour immune responses. This effect is mediated by increased production of IGFBP1, suggesting that galactose may offer a novel dietary approach to support cancer immunotherapy.

Epigenetic states are formed by the coordinated activity of several chromatin factors. Dam&ChIC recovers both past and current epigenetic states in single cells, revealing the timing and order of chromatin reorganization. It enabled us to identify how spatial chromatin localization is inherited upon mitosis, and to dissect successive chromatin remodeling events during the initiation of X-chromosome inactivation.

BLTP2 is a bridge-like lipid transport protein that operates at contacts between the endoplasmic reticulum and the plasma membrane. We show that phosphatidylethanolamine is transported to the plasma membrane by BLTP2, where it maintains membrane fluidity. Depletion of BLTP2 significantly impaired the metastasis of a triple-negative breast cancer cell line in xenografts.

Neutrophil infiltration during acute inflammation depends on leukotriene B₄ (LTB₄)-containing exosomes secreted via nuclear envelope-derived multivesicular bodies (MVBs). Co-secretion of nuclear DNA with these exosomes leads to temporal spikes in LTB₄ levels in inflamed tissue, activating the anti-inflammatory transcription factor PPARα and promoting neutrophil reverse migration. This facilitates neutrophil clearance and the resolution of inflammation.

After virus infection, RIG-I forms disulfide-linked oligomers that are resistant to degradation and able to enter liquid-like condensates, which is necessary for RIG-I-mediated stimulation of type I interferon signalling. RIG-I agonists and antagonists that enhance or prevent formation of disulfide-linked RIG-I oligomers, respectively, confirm that this mechanism is crucial for RIG-I function and could be harnessed to boost antiviral immunity or suppress autoimmunity caused by hyperactive RIG-I.

Cancers evade immunity in many ways, including by generating a metabolically hostile tumour microenvironment. Exposure of T cells to medium that mimics the metabolome of the tumour microenvironment resulted in potent T cell dysfunction. This dysfunction was induced via both depletion of arginine and exposure to phosphoethanolamine, which is a tumour-abundant metabolite that depletes T cells of diacylglycerol needed for signal transduction after tumour recognition.

We show that multipotent neural stem cells (NSCs) exist in the periphery and can be isolated from multiple peripheral tissues. Peripheral NSCs (pNSCs) are composed of SOX1⁺ cells that originate from neuroepithelial cells and not neural crest cells, share features with brain NSCs and contribute to peripheral neurogenesis during early development.

The existence of an endoplasmic reticulum (ER)–Golgi intermediate compartment (ERGIC) in plant cells has long been debated. In our study we identified a dynamic Golgi-independent tubular network that transports ER-derived cargos and interacts with pre-existing Golgi to mature into new pre-Golgi cisternae in a lipid-dependent manner.

We devised a multiomics strategy to identify metabolic pathways used by yeast to surmount mitochondrial stress. Strains capable of recovery relied on triacylglycerol mobilization to provide acyl groups for nascent cardiolipin biosynthesis during mitochondrial biogenesis. We further linked multiple proteins to this mobilization phenotype, including essential lipases in both yeast and mammalian model systems.

Blocking the translocase of the outer membrane (TOM) channel induces elimination of unoccupied protein import channels in the inner membrane by an ATP-dependent protease. Precursor-dependent adjustment of the number of translocator channels provides new insights into mitochondrial quality control upon protein import stress.

Combining genomics data from the TRACERx non-small-cell lung cancer (NSCLC) cohort and experimental data, we report that alterations in FAT1 are selected early during lung cancer evolution and cause chromosomal instability and whole-genome doubling.

We establish a mouse model of progressive diabetes induced by conditional NAT1 deficiency in vascular endothelial cells. NAT1 deficiency promotes the activation of RIPK1 owing to a type of post-translational modification mediated by spermidine and deoxyhyupisin synthase termed acetyl-hypusination. Our results suggest that inhibition of RIPK1 could be used to treat type 2 diabetes and vascular inflammation.

During early mouse development, a fluid-filled lumen inflates the embryo. Membrane protrusions called inverse blebs have been found to form at cell–cell contacts. Cycles of inverse bleb filling and unloading act as hydraulic pumps and contribute to the formation of the lumen.

Using single-cell RNA sequencing analysis of bone-colonizing tumour cells and in vivo screening, lymphotoxin-β (LTβ) was identified as a key factor promoting bone colonization and outgrowth of breast cancer metastases. Blocking LTβ signalling significantly suppressed bone metastasis, highlighting its potential as a therapeutic target for breast cancer with bone metastatic disease.