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Human pancreatic progenitor organoids define genetic and epigenetic barriers to early PDAC transformation
Dev Cell. 2026 May 19:S1534-5807(26)00159-0. doi: 10.1016/j.devcel.2026.04.012. Online ahead of print.
ABSTRACT
The lack of accurate human models that recapitulate pancreatic ductal adenocarcinoma (PDAC) initiation has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectories of tumor initiation and progression, validated against clinical datasets and tumor histopathology. We demonstrate that CDKN2A loss, which is nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, whereas SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of the pancreatic lineage program during PDAC initiation, alongside AP-1-driven chromatin remodeling. We identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and hypermethylation of essential pancreatic transcription factors. This model captures genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a potential early intervention strategy.
PMID:42161274 | PMC:PMC13196429 | DOI:10.1016/j.devcel.2026.04.012
De novo design of quasisymmetric two-component protein cages
Nature, Published online: 20 May 2026; doi:10.1038/s41586-026-10464-0
Researchers designed two-component proteins forming quasisymmetric cages via geometric frustration, enabling tunable virus-like assemblies for cargo delivery, cellular uptake and studying intracellular diffusion and protein localization.A Genetically Engineered Human Organoid Model Reveals Distinct Genetic and Epigenetic Barriers of Lineage Plasticity in Early PDAC Transformation
bioRxiv [Preprint]. 2026 Mar 11:2026.03.09.710586. doi: 10.64898/2026.03.09.710586.
ABSTRACT
The lack of accurate, human-based models recapitulating early-stage pancreatic ductal adenocarcinoma (PDAC) has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectory of tumor initiation and progression in vitro , validated against clinical datasets and histopathology. We demonstrate that CDKN2A loss, nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, while SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of pancreatic lineage program during PDAC initiation, alongside oncogenic AP-1-driven chromatin remodeling. Notably, we identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and the hypermethylation and silencing of essential pancreatic transcription factors. This model captures the genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a promising early intervention strategy for high-risk individuals.
PMID:41959451 | PMC:PMC13060829 | DOI:10.64898/2026.03.09.710586
Low-Bitrate Video Compression through Semantic-Conditioned Diffusion
Multi-ancestry transcriptome prediction with functionally informed variants in TOPMed MESA improves performance of transcriptome-wide association studies
Am J Hum Genet. 2026 Apr 2;113(4):828-841. doi: 10.1016/j.ajhg.2026.03.008.
ABSTRACT
Reliable reference transcriptome prediction models are key to accurate multi-ancestry transcriptome-wide association studies (TWASs). We propose three methods leveraging functionally informed variants (FIVs) for transcriptome prediction models to improve multi-ancestry TWASs. We trained models on 1,287 multi-ancestry participants from the Trans-Omics for Precision Medicine (TOPMed) program Multi-Ethnic Study of Atherosclerosis (MESA) with RNA sequencing (RNA-seq) data from peripheral blood mononuclear cells (PBMCs). We validated models' prediction accuracy on two external independent datasets, Geuvadis and Jackson Heart Study. To test robustness of our methods for TWASs, we integrated models with three multi-ancestry GWASs from blood cell, lipid, and pulmonary function traits, respectively. Our methods presented similar prediction accuracy while using a smaller and functionally informed set of variants compared to the benchmark method, elastic net (EN). Overall, our methods achieved higher power and accuracy (with average improved accuracy of 24% over EN) for TWASs. However, no single proposed method outperformed all GWAS traits. To further improve TWAS performance, we propose an omnibus approach that aggregates TWAS summary statistics from our methods. The omnibus approach yielded the highest number of Bonferroni-significant TWAS genes for all GWAS traits, and it further improved TWAS power and accuracy for blood cell traits. Additionally, the omnibus approach detected some trait-relevant important genes that the EN missed. Our study demonstrates the value of including FIVs in multi-ancestry transcriptome prediction models for improving TWAS performance. Further, the observed TWAS improvement depends on the GWAS trait's relevance to the PBMCs used to build our transcriptome prediction models.
PMID:41932314 | DOI:10.1016/j.ajhg.2026.03.008
Improving Ensemble Forecasts of Abnormally Deflecting Tropical Cyclones with Fused Atmosphere-Ocean-Terrain Data
Improving Ensemble Forecasts of Abnormally Deflecting Tropical Cyclones with Fused Atmosphere-Ocean-Terrain Data
Self-Improving Code Generation via Semantic Entropy and Behavioral Consensus
KEditVis: A Visual Analytics System for Knowledge Editing of Large Language Models
LPNSR: Prior-Enhanced Diffusion Image Super-Resolution via LR-Guided Noise Prediction
Cellular Senescence in Gastric Cancer: Molecular Mechanisms, Microenvironment Remodeling and Therapeutic Implications
Aging Dis. 2026 Mar 19. doi: 10.14336/AD.2025.1571. Online ahead of print.
ABSTRACT
Gastric cancer (GC) remains a leading cause of cancer-related morbidity and mortality worldwide, with poor prognosis for advanced-stage patients. Therefore, in-depth exploration of the mechanisms underlying GC initiation and progression, as well as the development of novel therapeutic strategies, is of crucial importance. Cellular senescence is a stable cell cycle arrest program that plays a dual role in GC. It exerts tumor-suppressive effects via growth arrest but also promotes tumor progression and immune evasion by remodeling the tumor microenvironment (TME) through senescence-associated secretory phenotype (SASP). This review comprehensively elucidates the molecular mechanisms of cellular senescence in GC and the core regulatory networks involving gene regulation, epigenetic modifications, metabolic reprogramming, and cell cycle arrest. Additionally, the review highlights how senescent cells foster an immunosuppressive microenvironment via SASP, forming a self-reinforcing feed-forward loop. Regarding therapeutic strategies, we summarize potential approaches targeting cellular senescence, including senescence induction, senescent cell clearance, SASP modulation, and multi-target synergistic therapy by integrating epigenetic regulation, metabolic intervention, and immune microenvironment modulation. Despite progress, numerous challenges remain. Future studies should leverage multi-omics technologies, novel models' development, and large-scale clinical trials to advance the clinical translation of GC cellular senescence research, providing new insights for improving prognosis.
PMID:41910653 | DOI:10.14336/AD.2025.1571
PhySe-RPO: Physics and Semantics Guided Relative Policy Optimization for Diffusion-Based Surgical Smoke Removal
LPNSR: Prior-Enhanced Diffusion Image Super-Resolution via LR-Guided Noise Prediction
Multimodal electron microscopy of halide perovskite interfacial dynamics
Nature, Published online: 11 March 2026; doi:10.1038/s41586-026-10238-8
A multimodal in situ electron microscopy approach enables direct visualization of structural and chemical evolution in a working halide perovskite light-emitting diode with nanometre precision.