bims-gerecp 2026-05-31 papers

bims-gerecp

Biomed News

on Gene regulatory networks of epithelial cell plasticity

Issue of 2026–05–31
sixteen papers selected by
Xiao Qin, University of Oxford

Evolving strategies for lineage tracing: Genetic markers, synthetic barcodes, and natural variants.
Screening for colorectal cancer.
Targeted single-cell RNA and perturbation sequencing with TAP-seq.
Decoding cellular population dynamics through mechanistic modelling and statistical data analysis.
Multiplexed perturbation enables scalable pooled screens.
Viral mimicry redirects immunosuppressed colorectal tumour landscapes towards a proinflammatory and CMS1-like regenerative state.
Uncovering spatially resolved functional genomics with CRISPR screen sequencing.
Multi Omics Integration in Colorectal Cancer: From Molecular Insights to Precision Oncology.
Mesenchymal drift: A convergent framework for the hallmarks of aging.
Computational blueprints for cell fate programming.
Single-cell analysis identifies dysregulated cell type-specific gene programs and intercellular crosstalk underlying colorectal cancer.
Gut microbial metabolites for potentiating cancer therapy.
Universal transcriptomic hallmarks of mammalian ageing and mortality.
Self-driving medicine: closed-loop therapeutics for autonomous disease control.
Advances in Immunotherapies for Targeting Cancer Stem Cells in a Tumor Microenvironment: Emerging Strategies and Clinical Prospects.
Synthetic DNA circuits for programming cell functions.

Cell Stem Cell. 2026 May 29. pii: S1934-5909(26)00193-1. [Epub ahead of print]

Evolving strategies for lineage tracing: Genetic markers, synthetic barcodes, and natural variants.

Zhixin Kang, Hui Chen, Siyang Li, Shou-Wen Wang, Bin Zhou.

  Elucidating cell fate decision-making requires linking lineage history to dynamic phenotypic states. Driven by single-cell sequencing and genome engineering, lineage tracing has evolved from observational studies into a multidimensional, high-throughput discipline. Here, we synthesize its three methodological pillars: prospective tracking via genetic markers, high-throughput mapping using synthetic barcodes, and retrospective tracing leveraging endogenous natural variants. We survey their integration with multi-omics and spatial profiling, alongside computational approaches to decode cell fates from lineage data. By detailing each approach's trade-offs, we offer a systematic guide for experimental design and highlight emerging frontiers for translating precision clonal analysis into the clinic.

Keywords:  barcoding; cell fate; development; diseases; lineage tracing; recombinase; regeneration

DOI:  https://doi.org/10.1016/j.stem.2026.05.001
CA Cancer J Clin. 2026 May-Jun;76(3):76(3): e70087

Screening for colorectal cancer.

DOI: https://doi.org/10.3322/caac.70087
Nat Protoc. 2026 May 26.

Targeted single-cell RNA and perturbation sequencing with TAP-seq.

Dewi P I Moonen, Daniel Schraivogel, Andreas R Gschwind, Lars M Steinmetz.

Pooled genome editing combined with single-cell RNA sequencing-commonly known as Perturb-seq-has transformed the ability to interrogate genome function. However, whole-transcriptome single-cell RNA sequencing requires high sequencing depth to achieve the sensitivity needed for functional genomics screens, limiting its widespread use owing to prohibitive cost. Here we describe a detailed and updated protocol for targeted Perturb-seq (TAP-seq), a method that addresses the sensitivity and cost limitations of Perturb-seq. Instead of capturing the whole transcriptome, TAP-seq focuses on quantifying hundreds of transcripts of interest. The TAP-seq workflow involves first selecting genes for targeted readout, designing primers, conducting an initial pilot experiment and finally performing the TAP-seq screen and analyzing the data. We provide comprehensive guidance on designing targeted readout strategies for TAP-seq and describe all steps of the protocol, starting with library preparation. The outcome of TAP-seq is single-cell measurements of selected gene and guide RNA expression levels, guide RNA assignments to individual cells and differential expression results revealing perturbation effects on target genes. We further include instructions for adapting TAP-seq to all currently available single-cell RNA-sequencing platforms. Prior experience in single-cell technologies is beneficial and the protocol described can be completed in 2 days (excluding data analysis). In summary, this protocol describes how to perform sensitive, scalable and cost-effective single-cell perturbation screens.

DOI: https://doi.org/10.1038/s41596-026-01367-5
NPJ Syst Biol Appl. 2026 May 25. pii: 73. [Epub ahead of print]12(1):

Decoding cellular population dynamics through mechanistic modelling and statistical data analysis.

Nissrin Alachkar, Nicholas Kwasi-Do Ohene Opoku, Nicholas A M Monk, Kevin Thurley.

Cell-cell communication underlies key processes in development, immunity, and disease, yet capturing its mechanistic complexity remains challenging. While advances in single-cell omics have revealed new insights into cell-type diversity, mathematical modelling has become essential for deriving mechanistic understanding of their communication networks. Here, we overview established modelling approaches and highlight the need for frameworks that move beyond steady-state assumptions and single-step processes, better reflecting the nature of cell-cell communication.

DOI: https://doi.org/10.1038/s41540-026-00751-x
Nat Methods. 2026 May 25.

Multiplexed perturbation enables scalable pooled screens.

Stefan Oberlin, Neil Q Tay, Albert Xue, Ruzbeh Mosadeghi, Harold Pimentel, Michael T McManus.

CRISPR-based genetic perturbation screens have revolutionized the ability to link genes to cellular phenotypes with unprecedented precision and scale; however, conventional pooled CRISPR screens require large cell numbers to achieve adequate sgRNA representation, posing technical and financial challenges. Here, we investigate the impact of co-delivery of multiple guide RNAs via high multiplicity of infection (MOI) in pooled CRISPR interference screens as a strategy to enhance screening efficiency while reducing cell numbers. We systematically evaluate screen performance across varying MOIs, assessing the effects of multiplexing on knockdown efficiency, sgRNA representation and potential interference of multiple sgRNA phenotypes. Our data demonstrate that sgRNA multiplexing (MOI 2.5-10) can maintain screen performance while enabling significant reductions in cell number requirements. We further apply these optimized conditions to conduct a genome-wide CRISPR screen for regulators of the intracellular adhesion molecule ICAM-1, successfully identifying new candidates using as few as half a million cells. This study provides a framework for adopting multiplexed sgRNA strategies to streamline CRISPR screening applications in resource-limited settings.

DOI: https://doi.org/10.1038/s41592-026-03095-w
Commun Biol. 2026 May 26.

Viral mimicry redirects immunosuppressed colorectal tumour landscapes towards a proinflammatory and CMS1-like regenerative state.

Shania M Corry, Svetlana Sakhnevych, Noha Ehssan Mohamed, Sudhir B Malla, Ryan Byrne, Andrew Young, Raheleh Amirkhah, Courtney Bull, Andrea Lees, Keara Redmond, Tamsin R M Lannagan, Rachel A Ridgway, Fiona R Taggart, Natalie C Fisher, Tim Maughan, Mark Lawler, Andrew D Campbell, Simon J Leedham, Aideen E Ryan, Daniel B Longley, Donna M Small, Owen J Sansom, Philip D Dunne.

In colorectal cancer (CRC), tumours classified as consensus molecular subtype 4 (CMS4) have the worst prognosis and derive negligible benefit from chemotherapy. We previously described how repressed interferon-related signalling is associated with increased relapse in CMS4 tumours. Although the viral mimetic polyinosinic:polycytidylic acid, poly(I:C), can reduce liver metastasis in vivo, the initial phenotypic changes that underpin its anti-metastatic response remain poorly described, particularly in the immunosuppressed CMS4 tumour microenvironment. Here we characterise lineage-specific anti-metastatic responses induced by poly(I:C), including acute macrophage polarisation and a novel CMS1-like regenerative stem cell state, which drive pro-inflammatory microenvironmental changes in CRC. These insights enabled the development of tractable biomarkers that identify an "immune-warm" patient subset most likely to respond to poly(I:C), enriched for mismatch-repair proficient (pMMR), anti-inflammatory macrophages and CMS4-like features. The viral mimetic poly(I:C) offers a tailored treatment option for poor-prognostic tumours, by reprogramming stem cell states and activation of an innate-adaptive anti-metastatic response.

DOI: https://doi.org/10.1038/s42003-026-10295-9
Cell. 2026 May 26. pii: S0092-8674(26)00516-7. [Epub ahead of print]

Uncovering spatially resolved functional genomics with CRISPR screen sequencing.

Haorui Zhang, Zongxu Zhang, Peiyu Wang, Tian Xu, Xiaoyu Chen, Yanping Zhao, Siyu Lin, Wenjie Cai, Pengfei Ren, Ce Luo, Peng Zhang, Yunfeng Wang, Sen Hou, Yahui Zhao, Hu Zeng, Zhihua Liu, Cunyu Wang, Zhidong Gao, Yu Feng, Deng Pan, Zexian Zeng.

  Spatial omics has advanced our understanding of tissue-level biology, yet tools to systematically link gene functional perturbations to spatial phenotypes and signaling pathways remain limited. To address this, we developed spatial CRISPR screen sequencing (SPAC-seq), a high-throughput spatial CRISPR screen platform, and TARDIS (target prioritization toolkit for perturbation data in spatial omics), a statistical spatial perturbation analysis toolkit. Using SPAC-seq and TARDIS, we linked gene perturbations to spatial phenotypes and pathways, uncovering how Icam1 loss in tumor cells promotes metastasis via immune suppression and macrophage polarization. In CD8+ T cells, we revealed Cd44's role in regulating spatial phenotypes by interacting with Spp1 on macrophages. We also demonstrated the model of the transcription factor-chemokine receptor axis coupling cell states with chemotaxis. SPAC-seq and TARDIS provide an effective framework to study spatially resolved functional genomics and pathways across diverse biological and disease contexts.

Keywords:  Cd44; Icam1; Spp1; cancer immunology; in vivo CRISPR screen; spatial CRISPR screen; spatial genomics; spatial perturbation analysis toolkit; spatial sequencing technology; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.cell.2026.04.049
Cancers (Basel). 2026 May 07. pii: 1504. [Epub ahead of print]18(10):

Multi Omics Integration in Colorectal Cancer: From Molecular Insights to Precision Oncology.

Zuoliang Liu, Mia Yang Ang, Chin Siang Kue.

  Colorectal cancer (CRC) is a biologically heterogeneous disease in which single-omics analyses incompletely capture the cross-layer mechanisms underlying tumor progression, immune evasion, and therapeutic resistance. This review critically examines how the integration of genomics, transcriptomics, proteomics, metabolomics, and microbiome profiling is redefining CRC biology and precision oncology. Landmark integrative efforts, including TCGA analyses of 276 colorectal cancer samples, CPTAC proteogenomic profiling of 95 tumors, and recent whole-genome sequencing studies of 2023 CRC cases, have refined molecular subtyping, expanded the driver landscape, and revealed clinically relevant discordance between mRNA abundance and protein activity. Integrative studies further show that oncogenic signaling may be driven by post-transcriptional and post-translational regulation, while spatially resolved profiling and microbiome-metabolite analyses are uncovering previously obscured tumor-microenvironment interactions. We also discuss how artificial intelligence-based approaches, including factor analysis, deep learning, graph-based models, and explainable AI, are improving subtype classification, biomarker discovery, and treatment-response prediction, with particular relevance to microsatellite instability-high and early-onset CRC. Finally, we critically evaluate the principal barriers to clinical translation, including batch effects, cross-platform variability, limited external validation, regulatory constraints, and cost, and outline priorities for building reproducible, clinically deployable multi-omics pipelines for CRC management.

Keywords:  artificial intelligence; biomarker discovery; colorectal cancer; consensus molecular subtypes; gut microbiota; liquid biopsy; multi-omics integration; proteogenomic; spatial transcriptomics

DOI:  https://doi.org/10.3390/cancers18101504
Cell. 2026 May 28. pii: S0092-8674(26)00455-1. [Epub ahead of print]189(11): 3184-3213

Mesenchymal drift: A convergent framework for the hallmarks of aging.

Jinlong Y Lu, William B Tu, Shuai Ma, Zaijun Ma, Ivan Imaz-Rosshandler, Mingxi Weng, Jing Qu, Concepcion Rodriguez Esteban, Pradeep Reddy, Guang-Hui Liu, Juan Carlos Izpisua Belmonte.

  Aging is characterized by the loss of tissue homeostasis, traditionally captured by the hallmarks of aging, yet how these hallmarks integrate to drive organismal decline remains unresolved. We propose mesenchymal drift, a process in which cells progressively lose lineage identity and adopt mesenchymal features, as a convergent framework that integrates the hallmarks of aging. Accumulating evidence suggests that mesenchymal drift can both arise from and reinforce these hallmarks, forming a feedback network that drives systemic decline. Framing aging through mesenchymal drift shifts the focus from discrete molecular defects to interconnected disruptions in cellular identity and cell state regulation, providing a more cohesive view of aging biology. Mesenchymal drift may therefore represent a measurable and targetable mechanism underlying diverse age-related pathologies. Interventions such as partial reprogramming may restrain mesenchymal drift, restore cellular identity, and simultaneously counteract multiple hallmarks, positioning it as both a convergent nexus and a tractable therapeutic axis in aging biology.

Keywords:  Yamanaka factors; aging; biomarkers; cellular identity and plasticity; endothelial-to-mesenchymal transition; epithelial-to-mesenchymal transition; fibrosis; geroscience; partial reprogramming; rejuvenation

DOI:  https://doi.org/10.1016/j.cell.2026.04.020
Stem Cell Reports. 2026 May 28. pii: S2213-6711(26)00140-2. [Epub ahead of print] 102929

Computational blueprints for cell fate programming.

Pengyi Yang.

  Cell fate programming enables applications in disease modeling, drug discovery, and regenerative medicine. Foundational studies established differentiation protocols, but their scalability is constrained by combinatorial complexity. Computational methods enable cell annotation, network inference, trajectory analysis, and have been applied to prioritize transcription factors and small molecules for cell fate programming, although prospective adoption for protocol design remains uneven. Single-cell and spatial omics, perturbation screens, and deep learning expand predictive scope while introducing challenges in domain shift, interpretability, and reproducibility. Here, I synthesize these approaches as pragmatic computational blueprints embedded in an iterative design-test-learn pipeline for cell fate programming.

Keywords:  ---

DOI:  https://doi.org/10.1016/j.stemcr.2026.102929
NPJ Precis Oncol. 2026 May 26.

Single-cell analysis identifies dysregulated cell type-specific gene programs and intercellular crosstalk underlying colorectal cancer.

Wenjing Jia, Kongxuan Lin, Xiumin Liu, Lingxiao Zou, Shan He, Jian Zhao, Jingjing Liu, Xiaofeng Song, Quan Wang, Yixuan Wang.

Colorectal cancer, a leading cause of cancer-related mortality, arises from the stepwise accumulation of genetic alterations in colonic epithelial cells, accompanied by dynamic remodeling of the tumor microenvironment. While the adenoma-carcinoma sequence is widely recognized, the cell type-specific gene programs and their interactions with the tumor microenvironment that drive malignant transformation remain poorly understood. In this study, we analyzed single-nucleus data from colorectal carcinoma and matched unaffected tissues, revealing dysregulated gene programs at the level of individual cell types. In epithelial cells, we identified two activated modules linked to enhanced stemness and two repressed modules associated with apoptosis and chronic inflammatory signaling. Transcription factors analysis highlighted CEBPB and RUNX1 as key activated regulators, while FOXP1 and POU5F1 were repressed in cancerous cells. Further investigation of intercellular communication uncovered disrupted crosstalk between epithelial cells and tumor microenvironment components, which may underlie these gene program alterations. Additionally, we observed functional reprogramming within the tumor microenvironment, including extracellular matrix remodeling by stromal fibroblasts and impaired B-cell-mediated immunity. Together, these findings improve our understanding of the molecular and cellular mechanisms driving colorectal tumorigenesis and may bring new opportunities for the development of therapeutic strategies.

DOI: https://doi.org/10.1038/s41698-026-01490-2
Trends Cancer. 2026 May 27. pii: S2405-8033(26)00080-4. [Epub ahead of print]

Gut microbial metabolites for potentiating cancer therapy.

Stephan Kamrad, Nicola Gagliani, Trevor D Lawley, Kiran R Patil, Joseph Tintelnot.

  The gut microbiome exerts distant and local effects on tumours, healthy epithelial cells, and the immune system through the production of bioactive metabolites. This influences cancer therapy responses across treatment modalities and cancer types. In this review, we discuss promising approaches to boost beneficial microbiota-derived metabolites to enhance existing cancer therapies, including prebiotics, probiotics, postbiotics, and live biotherapeutic products. Each approach faces challenges in achieving physiological concentrations and tissue distribution, as well as different regulatory regimes and commercial landscapes. With promising early clinical trials and significant scientific and commercial activity in these areas, there is hope that targeted, metabolite-focused interventions will soon benefit cancer patients.

Keywords:  LBPs; dietary supplements; metabolites; microbiome; probiotics; therapy response

DOI:  https://doi.org/10.1016/j.trecan.2026.04.005
Nature. 2026 May 27.

Universal transcriptomic hallmarks of mammalian ageing and mortality.

Alexander Tyshkovskiy, Daria Kholdina, Maria Davitadze, Adrian Molière, Alibek Moldakozhayev, Yoshiyasu Tongu, Tomoko Kasahara, Dmitrii Glubokov, Alec Eames, Leonid M Kats, Anastasiya Vladimirova, Kejun Ying, Hanna Liu, Bohan Zhang, Uma Khasanova, Mahdi Moqri, Jeremy M Van Raamsdonk, David E Harrison, Randy Strong, Takaaki Abe, Sergey E Dmitriev, Vadim N Gladyshev.

Ageing and interventions modulate health and mortality1, yet the underlying molecular mechanisms of this modulation remain unclear. Here we integrate more than 11,000 transcriptomes from more than 25 tissues across 4 mammals (mouse, rat, macaque and human) to develop accurate, interpretable rodent and multi-species biomarkers of chronological age and expected mortality, predicting lifespan-modulating interventions, time to death, chronic diseases and rejuvenation. Ageing-related changes were conserved across species and cell types, revealing universal transcriptomic signatures of mammalian ageing and mortality, including CDKN1A and LGALS3, whose protein levels were also associated with mortality and multimorbidity in UK Biobank. Mortality-associated features were recapitulated across in vivo and in vitro damage-accumulation models, including inflammation, replicative senescence, metabolic inhibition and γ-irradiation, and were attenuated or reversed by cell immortalization, reprogramming, heterochronic parabiosis and early embryogenesis. Network analysis uncovered a modular architecture of ageing- and mortality-associated hallmarks, encompassing inflammation, interferon signalling, mitochondrial function, chromatin modification and extracellular matrix organization. To quantify ageing of individual cellular components, we developed module-specific clocks, which revealed pathway-specific effects of interventions: chronic diseases primarily accelerated inflammatory-module ageing, whereas caloric restriction and Klotho (also known as Kl) deficiency targeted mitochondrial and metabolic modules. Transcriptomic and DNA methylation clocks showed correlated age acceleration in human blood, which was strongest for the chromatin-associated module clock, highlighting mechanistic links between molecular ageing modalities. This study reveals conserved signatures and a modular architecture of mortality regulation, providing a framework for quantifying and targeting ageing of cellular subsystems across species and tissues.

DOI: https://doi.org/10.1038/s41586-026-10542-3
Trends Biotechnol. 2026 May 28. pii: S0167-7799(26)00188-5. [Epub ahead of print]

Self-driving medicine: closed-loop therapeutics for autonomous disease control.

Gokberk Unal, Martin Fussenegger.

  Closed-loop gene circuits are paving the way toward self-driving medicine: therapeutics that continuously sense physiological signals, compute responses, and autonomously tune therapeutic output. Yet clinical practice still relies largely on open-loop dosing and static interventions that are inherently blind to real-time fluctuations in disease dynamics. Since Paracelsus, medicine has recognized that dose governs both efficacy and toxicity, but closed-loop therapeutics now redefine dose as a continuously computed response to physiology rather than as a fixed schedule. Enabled by synthetic biology, feedback-controlled therapeutics can be built from modular sensors, processors, and effectors to maintain homeostasis around defined physiological setpoints, moving therapy beyond intermittent interventions toward continuous sensing and adaptive control.

Keywords:  cell and gene therapy; feedback control; gene circuits; synthetic biology

DOI:  https://doi.org/10.1016/j.tibtech.2026.05.003
Cells. 2026 May 15. pii: 910. [Epub ahead of print]15(10):

Advances in Immunotherapies for Targeting Cancer Stem Cells in a Tumor Microenvironment: Emerging Strategies and Clinical Prospects.

Nakyung Oh, Van Ngu Trinh.

  Cancer stem cells (CSCs) are a distinct subpopulation within a tumor that play an important role in tumor initiation, metastasis, therapeutic resistance, and cancer relapse. Their persistence is strongly influenced by the tumor microenvironment (TME), which provides a range of biological signals that maintain stemness, promote immune evasion, and resistance to cancer treatment. Therefore, effective targeting of CSCs is essential to improve therapeutic efficacy. In this review, we summarize the key characteristics of CSCs and their niche within the TME, emphasizing their interactions with immune cells, stromal components, and secreted factors. We also discuss the major challenges in targeting CSCs, including immune evasion, metabolic constraints, and intratumoral heterogeneity. We further highlight current and emerging immunotherapeutic strategies targeting CSCs, including immune checkpoint inhibitors, cancer vaccines, monoclonal antibodies, nanobodies, bispecific antibodies, antibody-drug conjugates (ADCs), CAR-T and CAR-NK cell therapies, oncolytic viruses, as well as innovative approaches such as targeted protein degradation. Finally, we emphasize the importance of a combinatorial approach that integrates CSCs targeting with modulation of the TME. Together, these strategies may lead to more durable responses, enhance therapy efficacy and reduce the risk of tumor recurrence.

Keywords:  CAR-NK; CAR-T; antibody-drug conjugates (ADCs); bispecific antibody; cancer stem cells; cancer vaccines; immune checkpoint inhibitors; immunotherapy; monoclonal antibody; nanobodies; tumor microenvironment

DOI:  https://doi.org/10.3390/cells15100910
Curr Opin Chem Biol. 2026 May 29. pii: S1367-5931(26)00050-5. [Epub ahead of print]93 102701

Synthetic DNA circuits for programming cell functions.

Miao Wang, Wenfeng Tang, Siqi Jiang, Ping Wei.

Synthetic biology aims to re-engineer living cells into autonomous computational chassis capable of executing sophisticated biological tasks. Within this framework, programmable nucleic acid-based logic networks have emerged as a versatile molecular control layer for constructing intelligent cellular systems, offering unparalleled precision, orthogonality, and interoperability. Here, we highlight recent advances in molecular programming, focusing on the integration of synthetic DNA circuits within cellular environments to achieve logic-gated control of cellular functions. We first delineate the fundamental building blocks-including strand displacement, logic gates, amplifiers and neuromorphic architectures-and then examine strategies for interfacing these components with endogenous pathways. The field is currently witnessing a paradigm shift from ex vivo demonstration to in situ functional implementation, driven by the maturation of nucleic acid-based engineering within synthetic biology. Ultimately, these programmable molecular controllers enable the rational design of cellular behaviors, paving the way for next-generation precision therapeutics and autonomous biomanufacturing.

DOI: https://doi.org/10.1016/j.cbpa.2026.102701