bims-gerecp 2026-03-01 papers

bims-gerecp

Biomed News

on Gene regulatory networks of epithelial cell plasticity

Issue of 2026–03–01
twenty-one papers selected by
Xiao Qin, University of Oxford

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.
Genome-wide single-cell perturbation screens with VIPerturb-seq.
Single-cell ultra-high-throughput multiplexed chromatin accessibility and gene expression sequencing (SUM-seq).
Spatial perturb-seq: single-cell functional genomics within intact tissue architecture.
Beyond the chaos: How architecture structures tumour biology.
Charting single-cell lineages with synthetic and natural barcodes.
Reconstructing single-cell resolution from spatial transcriptomics with CellRefiner.
From laboratory bench to surgical room: Molecular profiling and single-cell technologies in precision surgery for colorectal cancer patients.
Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.
Chromatin accessibility landscapes define stromal cell identities across tissues.
Detecting microbial footprints in cancer sequencing.
Risk-based screening for early detection of colorectal cancer: an overview.
Microbiota-host interaction in colorectal cancer: emerging computational technology, multi-omics integration, and mechanisms.
Analysis of Combinatorial Knockout CRISPR Screens with GRAPE: Genetic interaction Regression Analysis of Pairwise Effects.
Mechanistic cancer prevention comes of age.
Is blood the new stool? Status of blood tests for CRC screening.
Diet-Driven Epigenetic Alterations in Colorectal Cancer: From DNA Methylation and microRNA Expression to Liquid Biopsy Readouts.
Macrophages: Targets for next-generation cancer immunotherapy.
Benchmarking LLM-based agents for single-cell omics analysis.
A disease model resource reveals core principles of tissue-specific cancer evolution.
Re-evaluating post-polypectomy surveillance: The role of non-invasive modalities in colorectal cancer prevention.

Science. 2026 Feb 26. 391(6788): eadw6273

Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging.

Ziyu Lu, Zehao Zhang, Zihan Xu, Abdulraouf Abdulraouf, Wei Zhou, Junyue Cao.

To investigate organism-wide cellular alterations and epigenomic dynamics during aging, we constructed a single-cell chromatin accessibility atlas spanning 21 mouse tissues across three age groups and both sexes. We found that around one-quarter of 536 organ-specific cell types and 1828 finer-grained subtypes exhibited considerable age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, indicating systemic signals that coordinate these changes. Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying these shifts. Moreover, ~40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.

DOI: https://doi.org/10.1126/science.adw6273
bioRxiv. 2026 Feb 13. pii: 2026.02.12.705613. [Epub ahead of print]

Genome-wide single-cell perturbation screens with VIPerturb-seq.

Alexandra Bradu, John D Blair, Isabella N Grabski, Isabella Mascio, Junsuk Lee, Cecilia McCormick, Rahul Satija.

CRISPR-based screening combined with single-cell sequencing (i.e. Perturb-seq) enables systematic mapping of genetic perturbations to molecular phenotypes. While Perturb-seq is well-suited to profile targeted subsets of regulators, scaling to genome-wide screens presents substantial cost and throughput challenges. Here we introduce VIPerturb-seq, a platform to facilitate routine genome-wide Perturb-seq experiments using probe-based detection workflows. We describe a split probe strategy for detection of genome-wide CRISPR libraries in fixed cells that enables (i) optional support for phenotypic enrichment of Very Important Perturbations (VIP) prior to single-cell profiling, and (ii) compatibility with combinatorial indexing workflows to further improve Perturb-seq throughput by 50-fold. Using a genome-wide CRISPRi library (GuEST-List), we demonstrate VIPerturb-seq on two genome-wide screens representing both unbiased and phenotypically enriched workflows. Our results demonstrate how the sensitivity, scalability, and efficiency of VIPerturb-seq can enable both individual labs with targeted research questions and large data generation platforms aiming to construct virtual cells.

DOI: https://doi.org/10.64898/2026.02.12.705613
Nat Protoc. 2026 Feb 26.

Single-cell ultra-high-throughput multiplexed chromatin accessibility and gene expression sequencing (SUM-seq).

Umut Yildiz, Sara Lobato-Moreno, Annique Claringbould, Hanke Gwendolyn Bauersachs, Nila H Servaas, Evi P Vlachou, Christian Arnold, Víctor Campos-Fornés, Karin D Prummel, Judith B Zaugg, Kyung Min Noh, Mikael Marttinen.

Single-cell epigenome and transcriptome profiling enables the dissection of gene regulatory networks, offering a powerful approach to characterize cellular heterogeneity and regulatory landscapes of cell states. Here we describe a single-cell ultra-high-throughput multiplexed sequencing (SUM-seq) assay for scalable and cost-effective simultaneous profiling of chromatin accessibility and gene expression in single nuclei. SUM-seq combines sample-specific accessible DNA and mRNA in situ barcoding with droplet-based microfluidic barcoding, introducing sample multiplexing and means to resolve multinucleated droplets for multiomic single-cell library preparation. In comparison with existing methods for multimodal profiling of chromatin accessibility and gene expression from the same cell, SUM-seq offers increased throughput and an unmatched multiplexing capability. This permits substantial scaling of the number of samples and nuclei assayed in one experiment, adhering to the needs of large-scale atlas projects, time-course experiments and perturbation screens while considerably reducing costs. We provide guidelines for experimental design and sample handling to accommodate various settings and sample types. Moreover, we discuss potential applications and provide guidelines for data processing. From sample collection to library preparation, the assay can be completed in 2-3 days, followed by sequencing and 1 day of data processing. Although the protocol can be implemented by researchers with general molecular biology skills, prior experience with single-cell assays is recommended.

DOI: https://doi.org/10.1038/s41596-025-01310-0
Nat Commun. 2026 Feb 21.

Spatial perturb-seq: single-cell functional genomics within intact tissue architecture.

Kimberle Shen, Wan Yi Seow, Choong Tat Keng, Michelle Gek Liang Lim, Daryl Shern Lim, Ke Guo, Amine Meliani, Muhammad Irfan Bin Hajis, Bolun Wang, Shyam Prabhakar, Kok Hao Chen, Wei Leong Chew.

We develop Spatial Perturb-Seq, an in vivo CRISPR technology that interrogates multiple genes within single cells of intact tissues, compatible with both sequencing-based and probe-based spatial technologies. We apply Spatial Perturb-Seq to knock out risk genes for neurodegenerative diseases in the mouse brain, uncovering cell autonomous and cell-cell microenvironmental effects within the spatially intact tissue. Spatial Perturb-Seq functionally screens multiple genes in situ and in vivo, bypasses cell processing steps that skew cell type representation, identifies intracellular and intercellular effects of knockouts, and identifies candidate genes underlying dysregulated neuronal intercellular communication pathways.

DOI: https://doi.org/10.1038/s41467-026-69677-6
FEBS J. 2026 Feb 22.

Beyond the chaos: How architecture structures tumour biology.

Lea Dörner, Catrin Lutz, Stefan Prekovic, Hendrik A Messal.

  Cancer is increasingly recognised as a complex and heterogeneous disease, shaped not only by genetic mutations but also by the physical and biochemical context in which tumours develop. The spatial position of a cell, including its physical, cellular and molecular surroundings, shapes its fate, phenotypic plasticity and potential to transform and drive tumour progression and evolution. Tissue architecture provides a powerful framework for understanding the complex dynamics of cancer. It integrates the structural organisation of the tumour and its surrounding tissue, the distribution of physical forces, biochemical niches, cellular neighbourhoods, and the broader tissue and organ context in which the tumour develops. Together, these elements form a dynamic and evolving landscape that is continuously remodelled through the multiscale communication of cellular, biochemical and mechanical components. Understanding the principles that govern these interactions reveals that cancer is not merely a chaotic aggregation of cells, but a patterned system shaped by coordinated spatial relationships. Here, we discuss the recent literature to examine how physical, biochemical and cellular relationships orchestrate tumour initiation, progression and treatment resistance, and how their collaboration acts not as a passive scaffold, but as the architect of tumour behaviour.

Keywords:  Tissue architecture; biochemistry; biophysics; cellular neighbourhoods; microenvironment; tumour biology

DOI:  https://doi.org/10.1111/febs.70470
Nat Rev Genet. 2026 Feb 27.

Charting single-cell lineages with synthetic and natural barcodes.

Alejo E Rodriguez-Fraticelli, Victoria Parreno.

Across our lifespan, cells divide and differentiate to create the functional units of all organs, yet with age and cancer a small number of cellular families (clones) will rule the fate of the organism. Advances in synthetic and natural barcoding methods now enable cellular ancestries to be reconstructed with unprecedented single-cell resolution. These single-cell lineage-tracing studies are leading to a re-evaluation of long-standing paradigms in development, ageing and cancer biology and are revealing the underpinnings of phenotypic heterogeneity for various cellular functions, including regeneration and stress responses. Despite remaining methodological challenges, progress continues towards multimodal tracing methods that combine spatial, genetic, epigenetic and transcriptomic information. The future transition of clonal analysis into the clinic may eventually help detect, predict and prevent disease progression.

DOI: https://doi.org/10.1038/s41576-026-00943-5
Nat Commun. 2026 Feb 27.

Reconstructing single-cell resolution from spatial transcriptomics with CellRefiner.

Eric Bourgain-Chang, Xiangyu Kuang, Zixuan Cang, Qing Nie.

Single-cell RNA sequencing technologies profile the transcriptome of individual cells but lack the spatial context necessary for dissecting cellular interactions like cell-cell communications. On the other hand, most current spatial transcriptomic technologies lack cellular resolution, limiting their capability for realistic downstream analysis. Here we present CellRefiner, a physical model-based method that integrates a single-cell dataset with a paired spatial dataset to generate single-cell resolution in the imputed spatial data. CellRefiner models cells as particles connected by forces, and then optimizes cell locations with spatial proximity constraints, gene expression similarity, and ligand-receptor interactions between cells. We systematically benchmark CellRefiner over a variety of simulated and real datasets using Visium, MERFISH, seqFISH, Slide-seqV2, and STARmap datasets to demonstrate its accuracy, robustness, and ability to recover spatial patterns of cells. We also demonstrate its utility for improving spatially dependent analysis over the original spatial data for the contact-based cell-cell communication on mouse cortex and lymph node tissues. Our results show CellRefiner is capable of reconstructing single-cell resolution from non-single-cell resolution spatial data, allowing downstream analysis that requires individual-cell resolution and spatial information.

DOI: https://doi.org/10.1038/s41467-026-70090-2
Surg Oncol. 2026 Feb 18. pii: S0960-7404(26)00033-2. [Epub ahead of print]65 102382

From laboratory bench to surgical room: Molecular profiling and single-cell technologies in precision surgery for colorectal cancer patients.

Maria Teresa De Angelis, Gianluca Santamaria, Angela Amaddeo, Antonio Maria Iannello, Giuseppe Viglietto, Antonia Rizzuto.

  Colorectal cancer (CRC) represents one of the major global health challenges, ranking among the top three leading causes of cancer-related mortality. Over the past decade, remarkable advances in molecular oncology, cancer genetics, and high-resolution single-cell technologies have reshaped the clinical landscape, refining prognostic frameworks and enabling new therapeutic opportunities. CRC is recognized as a heterogeneous disease driven by multiple pathways, including chromosomal instability (CIN), microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP). These canonical classification models have been expanded through whole-genome sequencing, which has allowed the identification of novel driver mutations, mutational signatures linked to environmental exposures as well as immune escape mechanisms with translational significance. The Consensus Molecular Subtypes (CMS) framework, along with the growing recognition of the importance of tumour location (sidedness), has influenced patient stratification and systemic treatment choice. At the same time, liquid biopsy technologies and organoid platforms have transformed preclinical modelling and perioperative surveillance. In this context, single-cell sequencing and spatial multi-omics have provided unprecedented resolution of intra-tumoral heterogeneity, stromal-immune crosstalk, and clonal dynamics during therapy, with direct implications for surgical oncology. This review synthesizes recent advances in CRC biology, highlights translational opportunities of organoid and single-cell technologies, and discusses their integration into perioperative strategies to support the concept of precision surgical in oncology. These advances increasingly position surgical resection as the final integrative step in translational oncology, where molecular profiling and functional modelling guide informed patient selection, operative timing, and perioperative treatment strategies.

Keywords:  Colorectal cancer; Liquid biopsy; Patient derived organoids; Precision medicine; Single-cell sequencing; Tailored surgery; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.suronc.2026.102382
bioRxiv. 2026 Feb 18. pii: 2026.02.12.705660. [Epub ahead of print]

Modeling mitochondrial inheritance enables high-precision single-cell lineage tracing in humans.

Teng Gao, Chen Weng, Isaac Johnson, Michael Poeschla, Jonas Gudera, Emily King, Christopher Rouya, Adriana Donovan, Lauren Bourke, Ying Shao, Eladio Marquez, Rahul Tyagi, Leonard I Zon, Jonathan S Weissman, Vijay G Sankaran.

Somatic mutations in mitochondrial DNA (mtDNA) provide natural barcodes that enable engineering-free lineage tracing in human tissues, but the complex dynamics of mtDNA inheritance across cell divisions and incomplete sampling of mtDNA introduce uncertainty in reconstructed lineages. Here, we present MitoDrift, a probabilistic framework that integrates Wright-Fisher drift dynamics with sparse single-cell measurements to produce confidence-refined lineage trees enriched for accurate clonal relationships. Validation with gold-standard lentiviral barcoding and whole-genome sequencing demonstrates that MitoDrift outperforms existing tree reconstruction methods in precision while maintaining high clonal recovery, enabling robust analyses linking lineage to cell state. Applying MitoDrift to human hematopoiesis reveals an age-associated decline in clonal diversity with differential impact across cell types and identifies heritable regulatory programs in hematopoietic stem cells in vivo, linking AP-1/stress-associated programs to clonal expansions. In multiple myeloma, MitoDrift captures therapy-associated clonal remodeling undetectable by copy number analysis, revealing phenotypic transitions and linking gene regulatory programs to differential drug sensitivity. Collectively, MitoDrift enables high-precision lineage tracing at scale and establishes quantitative lineage-state analysis in primary human tissues, linking clonal history to transcriptional and epigenetic programs in tissue homeostasis, aging, and disease.

DOI: https://doi.org/10.64898/2026.02.12.705660
Commun Biol. 2026 Feb 25.

Chromatin accessibility landscapes define stromal cell identities across tissues.

Amin Nooranikhojasteh, Ghazaleh Tavallaee, Nicholas Khuu, Shu Yi Shen, Shaida Ouladan, Ayush Raman, Elias Orouji.

Chromatin accessibility is crucial in regulating gene expression and maintaining cellular identity. While single-cell RNA sequencing has revolutionized transcriptomic profiling, the understanding of chromatin dynamics across diverse tissues remains limited. Here, we use single-cell Assay for Transposase-Accessible Chromatin sequencing (scATAC-seq) to explore chromatin accessibility landscapes across murine tissues. We profile chromatin accessibility in 51,248 cells from nine mouse tissues, identifying 28 major cell types with distinct accessibility signatures. Our data reveal both conserved and tissue-specific cis-regulatory elements, highlighting the dynamic interplay between transcription factors and chromatin states in cell differentiation and tissue function. Motif enrichment analyses uncover transcription factor motifs driving these regulatory landscapes. Notably, we demonstrate that chromatin accessibility profiles enable tracing stromal cells, including endothelial cells, fibroblasts, and macrophages back to their tissue of origin. Using a metacell approach, we identify specific chromatin modules reflecting tissue-specific epigenomic landscapes, underscoring the role of chromatin accessibility in defining stromal cell identities. Our study provides a comprehensive atlas of chromatin accessibility across murine tissues, offering insights into the regulatory architecture that governs tissue and cell-type specificity. The ability to trace stromal cells to their tissue of origin through chromatin signatures holds important implications for diagnostics and therapeutic interventions in disease contexts.

DOI: https://doi.org/10.1038/s42003-026-09720-w
Cancer Cell. 2026 Feb 26. pii: S1535-6108(26)00102-9. [Epub ahead of print]

Detecting microbial footprints in cancer sequencing.

Gianmarco Piccinno, Robin Mjelle, Nicola Segata.

Detecting the presence of microbial organisms within the tumor microenvironment may have biomedical relevance but presents serious technical challenges. In this issue of Cancer Cell, Ghaddar et al. develop a computational framework for the reliable detection of microbes within tumoral genomic and transcriptomic data.

DOI: https://doi.org/10.1016/j.ccell.2026.02.005
Best Pract Res Clin Gastroenterol. 2026 Feb;pii: S1521-6918(25)00041-1. [Epub ahead of print]80 102014

Risk-based screening for early detection of colorectal cancer: an overview.

Chiara C Brück, Lucy W Mwangi, Francine van Wifferen, Li Hsu, Minta Thomas, Ulrike Peters.

Screening programs for colorectal cancer (CRC) reduce CRC incidence and mortality, while balancing benefits and harms of the population. However, benefits vary widely among individuals. Low-risk individuals may face unnecessary burdens, while high-risk individuals could benefit from more intensive screening. Risk-based screening addresses these issues by tailoring screening strategies using risk factors such as age, sex, race, ethnicity, lifestyle factors, genetic predisposition, and previous screening results. Potential benefits of risk-based screening include improved cost-effectiveness, efficient resource use and reduced unnecessary procedures. Challenges include a lack of validated risk stratification tools, data availability, healthcare capacity, and ethical considerations. Several countries started to evaluate risk-based screening programs with optimistic results. While promising, further research is necessary to address the remaining challenges. Nevertheless, risk-based screening has the potential to enhance patient experiences, optimize the balance of individual-level benefits and harms, and positively impact the overall burden and costs associated with CRC screening.

DOI: https://doi.org/10.1016/j.bpg.2025.102014
Cancer Biol Med. 2026 Feb 23. pii: j.issn.2095-3941.2025.0762. [Epub ahead of print]

Microbiota-host interaction in colorectal cancer: emerging computational technology, multi-omics integration, and mechanisms.

Yinghong Lu, Jun Yu.

  Colorectal cancer (CRC) remains a major global health burden with the gut microbiome emerging as a critical contributor to tumor initiation and progression. Advances in high-throughput sequencing have deepened our understanding of host-microbe interactions across genomic, transcriptomic, epigenomic, and metabolomic levels. This review synthesizes current knowledge on how microbial communities shape colorectal carcinogenesis, including induction of genomic instability, remodeling of host transcriptional and epigenetic landscapes, and reprogramming of metabolic pathways within the tumor microenvironment. Integrative multi-omics strategies and advanced computational tools are powerful means for dissecting these complex biological systems. However, analytical challenges, such as data compositionality, sparsity, and high dimensionality, still hinder meaningful interpretation. Emerging technologies, like long-read sequencing and bacterial single-cell spatial transcriptomics, are enhancing the resolution and accuracy of microbiota profiling. Finally, the convergence of advanced experimental models, artificial intelligence-driven computational integration, and precision microbiome medicine are highlighted as key avenues for translating microbiome insights into preventive, diagnostic, and therapeutic innovations in CRC.

Keywords:  Colorectal cancer; bioinformatics; high-throughput sequencing; microbiota; multi-omics integration

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2025.0762
bioRxiv. 2026 Feb 11. pii: 2026.02.09.704894. [Epub ahead of print]

Analysis of Combinatorial Knockout CRISPR Screens with GRAPE: Genetic interaction Regression Analysis of Pairwise Effects.

Juihsuan Chou, Chenchu Lin, Subin Kim, Junjie Chen, Traver Hart.

Genetic interactions (GI) reveal functional relationships for understanding gene function and identifying candidate therapeutic vulnerabilities. Combinatorial CRISPR technologies enable genome-scale GI mapping in mammalian cells, but existing analytical methods lack systematic validation against ground truths. We introduce GRAPE (Genetic interaction Regression Analysis of Pairwise Effects), a computational framework that identifies GIs from pooled CRISPR screens by using linear regression to estimate single-gene phenotypes and detecting deviations from expected double-knockout effects. To enable rigorous benchmarking, we developed Synulator, a pipeline that simulates realistic CRISPR screen data with defined synthetic lethal interactions while preserving experimental noise profiles. In simulated screens, GRAPE achieves greater precision and recall compared to existing methods, particularly for interactions with weaker effect sizes. Applying GRAPE to published combinatorial screens across cell lines and CRISPR platforms demonstrates concordance with original findings while identifying additional high-confidence interactions. GRAPE provides a robust, versatile tool for GI mapping, advancing functional genomics and the systematic discovery of synthetic lethal targets in cancer.
Teaser: A regression-based framework and simulations enable accurate detection of GIs from combinatorial CRISPR screens.

DOI: https://doi.org/10.64898/2026.02.09.704894
Trends Cancer. 2026 Feb 23. pii: S2405-8033(26)00002-6. [Epub ahead of print]

Mechanistic cancer prevention comes of age.

Anbalakan Paramasivam, David Crosby, Joanna Janus, Phil Prime.

  Historically underfunded and dominated by epidemiological and behavioural research, cancer prevention is now able to embrace mechanistic insights that enable targeted, biologically grounded interventions. As a new generation of mechanistically based strategies begins to take shape, cancer prevention is poised to enter a new era.

Keywords:  cancer prevention; mechanistic cancer prevention

DOI:  https://doi.org/10.1016/j.trecan.2026.01.002
Best Pract Res Clin Gastroenterol. 2026 Feb;pii: S1521-6918(25)00076-9. [Epub ahead of print]80 102049

Is blood the new stool? Status of blood tests for CRC screening.

Erin L Symonds, Maddison Dix, Molla M Wassie, Norma B Bulamu, Graeme P Young, Jean M Winter.

  Colorectal cancer (CRC) screening has proven to decrease CRC incidence and mortality, with many countries providing faecal immunochemical tests (FIT) in screening programs. Effectiveness, however, is limited in the setting of low participation rates, which has prompted growing research into blood-based screening. While blood testing is anticipated to improve participation due to greater population acceptability, its readiness for widespread implementation remains unclear, and comparative accuracy data against FIT is needed. This article provides a systematic review and meta-analysis on blood-based CRC screening tests that have been directly compared to FIT, and summarises the evidence for broader program considerations, including analytical quality, consumer preferences, participation rates and cost effectiveness. The findings show that blood tests currently lack the sensitivity and cost-effectiveness to replace FIT in screening programs, and that their use should be limited to individuals unable or unwilling to complete FIT.

Keywords:  Accuracy; Blood; Circulating tumour DNA; Colorectal cancer; Faecal immunochemical test; Screening; Sensitivity; Specificity

DOI:  https://doi.org/10.1016/j.bpg.2025.102049
Biomedicines. 2026 Jan 24. pii: 267. [Epub ahead of print]14(2):

Diet-Driven Epigenetic Alterations in Colorectal Cancer: From DNA Methylation and microRNA Expression to Liquid Biopsy Readouts.

Theodora Chindea, Alina-Teodora Nicu, Gheorghe Dănuț Cimponeriu, Bianca Galateanu, Ariana Hudita, Mirela Violeta Șerban, Remus Iulian Nica, Liliana Burlibasa.

  The escalating incidence of colorectal cancer (CRC), particularly the alarming rise in early-onset cases, necessitates a paradigm shift from a purely genetic perspective to a broader investigation of promising pathways. This review explores the "nutri-epigenetic" interface, positioning liquid biopsy as a critical technology for translating dietary impacts into actionable clinical biomarkers. We contrast the molecular consequences of the Western dietary pattern, characterized by methyl-donor deficiency and pro-inflammatory metabolites, with the protective mechanisms of the Mediterranean diet. Mechanistically, we detail how Western-style diets drive a specific "epigenetic double-hit": promoting global DNA hypomethylation (destabilizing LINE-1) while paradoxically inducing promoter hypermethylation of critical tumour suppressors (MLH1, APC, MGMT) and silencing tumour-suppressive microRNAs (miR-34b/c, miR-137) via methylation of their encoding genes. Conversely, we highlight the capacity of Mediterranean bioactive compounds (e.g., resveratrol, curcumin, butyrate) to inhibit DNA methyltransferases and restore epigenetic homeostasis. Bridging molecular biology and clinical utility, we demonstrate how these diet-sensitive signatures, specifically circulating methylated DNA and dysregulated microRNAs, can be captured via liquid biopsy. We propose that these circulating analytes serve as dynamic, accessible biomarkers for monitoring the molecular progression toward a carcinogenic state, thereby establishing a novel framework for personalized risk stratification and validating the efficacy of preventive nutritional strategies.

Keywords:  DNA methylation; Mediterranean diet; Western diet; bioactive compounds; colorectal cancer; epigenetic biomarkers; liquid biopsy; methylated microRNAs; microRNA

DOI:  https://doi.org/10.3390/biomedicines14020267
Cancer Cell. 2026 Feb 26. pii: S1535-6108(26)00059-0. [Epub ahead of print]

Macrophages: Targets for next-generation cancer immunotherapy.

Xiaoqi Sun, Matthew D Park, Miriam Merad, Brian D Brown.

  Tumor-associated macrophages (TAM) are among the most abundant immune cells in tumors and exhibit striking functional plasticity, enabling them to either promote tumor progression or mediate malignant cell elimination. This paradox arises from TAM heterogeneity shaped by diverse developmental origins, transcriptional programs, and microenvironmental cues. Here, we review next-generation strategies to therapeutically target TAMs, with dual goals of relieving macrophage-driven immunosuppression and unleashing their tumoricidal potential. These approaches include effectorization by modulating "eat-me" pathways and targeted activation, as well as reprogramming TAMs through inhibiting immune checkpoints, rewiring signaling, epigenetics, and metabolism, and targeting myeloid progenitors at sites of hematopoiesis. We also discuss advances in bioengineering, including bispecific antibodies, masked cytokines, genetic engineering, targeted lipid nanoparticles and anti-TAM CAR T cells, that enable increasingly precise control of macrophage biology. These therapies have transformative potential to enhance tumor-specific T cells, and provide an independent alternative arm of immunity, to enable durable cancer eradication.

Keywords:  cancer immunotherapy; immune oncology; macrophages; myeloid therapies; tumor immunology; tumor macrophages

DOI:  https://doi.org/10.1016/j.ccell.2026.01.020
Genome Biol. 2026 Feb 25.

Benchmarking LLM-based agents for single-cell omics analysis.

Yang Liu, Lu Zhou, Xiawei Du, Ruikun He, Xuguang Zhang, Rongbo Shen, Yixue Li.

   BACKGROUND: The surge in single-cell omics data exposes limitations in traditional, manually defined analysis workflows. AI agents offer a paradigm shift, enabling adaptive planning, executable code generation, traceable decisions, and real-time knowledge fusion. However, the lack of a comprehensive benchmark critically hinders progress.
RESULTS: We introduce a novel benchmarking evaluation system to rigorously assess agent capabilities in single-cell omics analysis. This system comprises: a unified platform compatible with diverse agent frameworks and LLMs; multidimensional metrics assessing cognitive program synthesis, collaboration, execution efficiency, bioinformatics knowledge integration, and task completion quality; and 50 diverse real-world single-cell omics analysis tasks spanning multi-omics, species, and sequencing technologies. Our evaluation reveals that Grok3-beta achieves state-of-the-art performance among tested agent frameworks. Multi-agent frameworks significantly enhance collaboration and execution efficiency over single-agent approaches through specialized role division. Attribution analyses of agent capabilities identify that high-quality code generation is crucial for task success, and self-reflection has the most significant overall impact, followed by retrieval-augmented generation (RAG) and planning.
CONCLUSIONS: This work highlights persistent challenges in code generation, long-context handling, and context-aware knowledge retrieval, providing a critical empirical foundation and best practices for developing robust AI agents in computational biology.

Keywords:  Benchmarking evaluation system; LLM-based agents; Single-cell omics analysis

DOI:  https://doi.org/10.1186/s13059-026-03998-z
Nature. 2026 Feb 25.

A disease model resource reveals core principles of tissue-specific cancer evolution.

Sebastian Mueller, Niklas de Andrade Krätzig, Markus Tschurtschenthaler, Miguel G Silva, Chiara Thordsen, Riccardo Trozzo, Perrine Simon, Frederic Saab, Thorsten Kaltenbacher, Magdalena Zukowska, Daniele Lucarelli, Rupert Öllinger, Joscha Griger, Nina Groß, Tanja Groll, Jessica Löprich, Antonio E Zaurito, Linus R Schömig, Jeroen M Bugter, Stefanie Bärthel, Chiara Falcomatà, Alexander Strong, Cordelia Brandt, Mulham Najajreh, Aristeidis Papargyriou, Roman Maresch, Katharina A N Collins, David Sailer, Christian Schneeweis, Sebastian Burger, Lisa M Fröhlich, Christine Klement, Alexander Belka, Juan J Montero, Ute Jungwirth, Maximilian Reichert, Markus Moser, Jens Neumann, George Vassiliou, Juan Cadiñanos, Ignacio Varela, Carsten Marr, Daniel F Alonso, Pier-Luigi Lollini, Jean Zhao, Louis Chesler, Clare M Isacke, Angela Riedel, Christian J Braun, Martin L Sos, Filippo Beleggia, Hans C Reinhardt, Monica Musteanu, Mariano Barbacid, Michael Quante, Marc Schmidt-Supprian, Günter Schneider, Simon Clare, Trevor D Lawley, Gordon Dougan, Katja Steiger, Nathalie Conte, Allan Bradley, Lena Rad, Dieter Saur, Roland Rad.

Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved1-5. Here, to address these questions, we developed the Mouse Cancer Cell line Atlas, a broad-utility resource of 590 comprehensively characterized models across a wide range of entities ( www.mcca.tum.de ). Comparative and functional studies using this platform, human cohorts and mice identified core principles underlying tissue-specific evolution of KRAS-initiated cancers. First, we show that mutant KRAS dosage gain through allelic imbalance exerts cell-type-specific effects, defining its timing across entities, as exemplified by dosage-sensitive developmental reprogramming during pancreatic cancer initiation. Second, we highlight how tissue- and stage-specific evolutionary requirements, such as block of differentiation in the intestine, select for KRAS-collaborating alterations. Third, we identified context-dependent epistatic KRAS-tumour suppressor interactions and show that reciprocal dosage sensitivities dictate the entity-specific patterns of cancer gene alterations, explaining their frequency, zygosity and acquisition chronology. These findings highlight how intrinsic and acquired determinants instruct cancer evolution in different tissues, with predictable molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes.

DOI: https://doi.org/10.1038/s41586-026-10187-2
Best Pract Res Clin Gastroenterol. 2026 Feb;pii: S1521-6918(26)00002-8. [Epub ahead of print]80 102092

Re-evaluating post-polypectomy surveillance: The role of non-invasive modalities in colorectal cancer prevention.

Ethna McFerran, Damian McKay, Maurice B Loughrey, Mark Lawler, Stephen T McSorley.

Post-polypectomy surveillance is a cornerstone of colorectal cancer (CRC) prevention, yet current reliance on colonoscopy poses challenges related to capacity, patient burden, and adherence. Amid growing interest in non-invasive strategies, this review evaluates the diagnostic performance, clinical applicability, and limitations of emerging alternatives, including faecal immunochemical testing (FIT), multitarget stool DNA (mt-sDNA), CT colonography (CTC), circulating tumour DNA (ctDNA), and colon capsule endoscopy (CCE), in the context of post-polypectomy surveillance. While FIT remains widely endorsed for low-risk populations, its limited sensitivity for flat adenomas and serrated lesions constrains its utility. mt-sDNA and CTC offer incremental improvements in detection but face cost-effectiveness, false-positive, and guideline limitations in surveillance. ctDNA holds promise for recurrence monitoring in high-risk CRC but remains investigational for adenoma surveillance. Evidence for CCE as a triage tool is emerging, though concerns persist regarding incomplete examinations, cost, and residual risk. Importantly, substantial heterogeneity in surveillance guidelines and suboptimal real-world adherence complicate evaluation and implementation of these modalities. Integration of molecular biomarkers and risk-adaptive strategies may support more personalised follow-up. However, robust comparative effectiveness studies that account for system-level and behavioural factors are essential to guide appropriate adoption. Non-invasive tools remain complementary, not yet replacements, for colonoscopy in post-polypectomy care.

DOI: https://doi.org/10.1016/j.bpg.2026.102092