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  1. قبل ٨ ساعات

    990-Mechanisms of RAS Inhibitor Resistance

    This research identifies how cancer cells develop resistance to tri-complex inhibitors (TCIs), which are molecular glues designed to neutralize oncogenic RAS signaling. By analyzing patient samples and preclinical models, the authors discovered that specific mutations disrupt the RAS-inhibitor-CYPA synthetic complex. Some alterations, like those at KRAS residue Y64, physically prevent the drug from binding to the RAS protein. Conversely, mutations such as KRAS Y71H or hypoactive BRAF increase the natural affinity between RAS and its effectors, making it harder for the drug to displace them. The study highlights these convergent resistance pathways to inform the development of next-generation inhibitors and better combination therapies. These findings provide a structural and mechanistic framework for overcoming evasion strategies in RAS-driven malignancies. References: Sang B, Ye L, Fu Z ... Disrupted molecular glue complex drives RAS inhibitor resistance. Cell, 2026; 0

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  2. قبل ٩ ساعات

    989-Biogeography of Multi-Kingdom Cancer Microbiome

    This paper presents PathSeq-T2T, a highly precise computational pipeline designed to identify microbial DNA within human tumor samples while rigorously removing host genetic material and environmental contaminants. By applying this technology to over 16,000 cancer genomes, researchers discovered that orodigestive cancers—such as those in the mouth, stomach, and colon—harbor complex, multi-kingdom communities including bacteria, fungi, and rare parasites. Conversely, most other solid tumor types lack a detectable microbiome once background noise is properly eliminated. The study reveals that tumor mutation burden (TMB) is a primary predictor of microbial presence, with hypermutated cancers showing significantly higher levels of colonization. Furthermore, specific microbial shifts were identified in early-onset colorectal cancers, highlighting potential links between the microbiome and cancer development in younger patients. Ultimately, this research provides a high-resolution atlas that clarifies the specific types of cancer influenced by resident microorganisms. References: Dohlman A B, Mjelle R, Wood H M, et al. Biodiversity and biogeography of the multi-kingdom cancer microbiome[J]. Cancer Research, 2026, 86(7_Supplement): 4901-4901.

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  3. قبل ٩ ساعات

    988-Multi-Embed: Decoding Pathological Morphologies

    The paper introduces Multi-Embed, a new computational framework designed to bridge the gap between physical disease structures and complex molecular data. While traditional methods often struggle with transparency or limited data scales, this self-supervised learning tool creates a shared digital space to align tissue images with genetic and protein profiles. By utilizing an auto-encoder architecture and contrastive learning, it successfully identifies intricate tissue patterns and predicts disease progression across a variety of cancers. The researchers demonstrate that this approach is both interpretable and highly adaptable for large clinical studies. Ultimately, the framework provides a more comprehensive way to decode the relationship between how a disease looks and its underlying biological mechanisms. References: Zhang P, Gao C, Hua K, et al. Systematically decoding pathological morphologies and molecular profiles with unified multimodal embedding[J]. Nature Methods, 2026: 1-6.

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  4. قبل ١٠ ساعات

    987-The Metaphyseal Niche Governs Leukaemic Stem Cell Fate

    The research examines how the spatial positioning of leukaemic stem cells (LSCs) within different bone marrow regions fundamentally dictates their survival and disease progression. Studies using mouse models demonstrate that LSCs remain quiescent and stem-like when localized in the metaphysis, whereas moving to the central marrow induces cell-cycle activity and therapeutic vulnerability. This localization is controlled by a complex chemical signaling axis involving the enzymes DPP4 and GPC3, which regulate gradients of the chemoattractant CXCL12. Specifically, DPP4 deficiency or inhibition disrupts these gradients, forcing LSCs out of their protective niches and trapping them within the bone marrow to prevent systemic spread. The researchers conclude that targeting this regulatory pathway causes LSC exhaustion and significantly enhances the effectiveness of acute myeloid leukaemia treatments. By identifying N-cadherin+ stromal cells as the key producers of these supporting signals, the study offers a precise roadmap for future clinical interventions. References: Wang C, Pan Y, Dong R, et al. Longitudinal localization of leukaemic stem cells between the metaphysis and central marrow governs their behaviour[J]. Nature Cell Biology, 2026: 1-13.

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  5. قبل ١٠ ساعات

    986-Transgene-Free Human Peri-Gastrulation Embryo Models

    This technical report introduces a transgene-free human embryo model known as the peri-gastrulation trilaminar embryonic disc (PTED) embryoid. Created from primed human pluripotent stem cells, these 3D structures successfully mimic the self-organizing properties of the critical human peri-gastrulation phase. The models feature a trilaminar disc situated between an amniotic-like sac and a yolk sac-like structure, effectively replicating early embryonic and extraembryonic development. Researchers utilized BMP4 induction and geometric confinement to trigger differentiation into major germ layers and primitive haematopoiesis. These findings suggest that the human epiblast retains the potential to contribute to extraembryonic lineages during this stage. Ultimately, PTED embryoids provide an ethically accessible tool for studying the fundamental mechanisms of early human life. References: Sun S, Zheng Y, Kim Y S, et al. A transgene-free, human peri-gastrulation embryo model presents trilaminar embryonic disc-, amnion-and yolk sac-like structures[J]. Nature Cell Biology, 2026: 1-17.

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  6. قبل ١١ ساعة

    985-Organellar Insights in Ageing and Longevity

    These sources examine the critical role of cellular organelles in controlling ageing and lifespan. Researchers highlight how lysosomes, mitochondria, and the endoplasmic reticulum function as metabolic signalling hubs that maintain cellular balance. The text details how these structures communicate through dynamic crosstalk and inter-tissue signalling to influence organismal fitness. Beyond internal processes, the research explores how organelle interactions regulate microbiome-host relations and the transgenerational inheritance of longevity. Finally, the authors evaluate how longevity-promoting interventions, such as dietary restriction and pharmacological treatments, specifically target organelle health to delay age-related decline. References: Mannino P, Park M, Wang M C. Organellar insights in ageing and longevity[J]. Nature Cell Biology, 2026: 1-14.

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  7. قبل ١١ ساعة

    984-Restrictions of Cell Competition in Mosaic Gastruloids

    This research utilizes mouse gastruloids as a three-dimensional model to investigate cell competition during early mammalian development. By introducing p53-deficient supercompetitor cells into wild-type populations, the authors demonstrate that even a tiny fraction of these aggressive cells can trigger mitochondrial apoptosis in their neighbors. The study identifies a specific temporal window—the transition from pluripotency to early gastrulation—where this competitive selection is most active. Unlike two-dimensional cultures that rely on resource limitation, this 3D embryonic model reveals that competition is driven by relative p53 protein levels and intrinsic stress signals. These findings establish that cell fitness evaluation is a tightly regulated quality control mechanism necessary for maintaining embryonic integrity. Ultimately, the work positions gastruloids as a powerful tool for studying how mammalian embryos eliminate suboptimal cells to ensure healthy development. References: Frenster J D, Babin S, Casani-Galdon P, et al. Mosaic gastruloids reveal a temporal restriction for developmental cell competition[J]. Nature Cell Biology, 2026: 1-15.

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  8. قبل ١٢ ساعة

    983-Lipid-CLEM: Visualizing Nanoscale Lipid Distribution

    The paper describes the development of Lipid-CLEM, a novel imaging workflow designed to visualize the nanoscale distribution of specific lipid molecules within cellular membranes. By combining minimally modified bifunctional lipid probes with correlative light and electron microscopy, researchers can now quantify lipid densities across suborganellar structures with high precision. This method overcomes traditional limitations in lipid imaging, such as rapid molecular movement and localization artifacts caused by bulky fluorescent tags. Using this technique, the study demonstrates that sphingomyelin is actively sorted within the early endosome, showing significant enrichment in intraluminal vesicles and depletion in recycling tubules. These findings reveal that lipids, much like proteins, exhibit highly organized partitioning that is critical for intracellular trafficking and signaling. Ultimately, Lipid-CLEM provides a powerful new tool for exploring the complex, ultrastructural functions of lipids in living systems. References: Lennartz H M, Khan S, Leng W, et al. Visualizing suborganellar lipid distribution using correlative light and electron microscopy[J]. Nature Cell Biology, 2026: 1-10.

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