bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–12–21
nineteen papers selected by
Xiao Qin, University of Oxford
  1. Systematic scRNA-seq screens profile neural organoid response to morphogens.
  2. Carta offers a computational approach to inference of differentiation maps from cell lineages.
  3. Tumor Cell Plasticity in Cancer: Signaling Pathways and Pharmaceutical Interventions.
  4. Building dynamical models of multi-step state transitions from single cell gene expression trajectories.
  5. Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer.
  6. Dissecting how morphogens shape cell fates in human neural organoids.
  7. Regulatory element modules as universal features for single-cell chromatin analysis.
  8. Harnessing LLMs to decode genetic perturbations.
  9. Metabolic Adaptation in Colorectal Cancer Microenvironment: Focus on Cancer-Associated Fibroblasts (CAFs) and Tumor-Associated Macrophages (TAMs).
  10. LARIS enables accurate and efficient ligand and receptor interaction analysis in spatial transcriptomics.
  11. Early mutational events and clonal dynamics in normal crypts: implications for colorectal tumorigenesis.
  12. Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.
  13. Multistep genomics on single cells and live cultures in subnanoliter capsules.
  14. Methods to analyze cell migration data: fundamentals and practical guidelines.
  15. Mapping human neurodevelopment-Brain organoids meet lineage tracing.
  16. Selecting the optimal cell migration assay: fundamentals and practical guidelines.
  17. Tumor-infiltrating Bacteria Induce Quiescence and Therapy Resistance.
  18. FastCCC: a permutation-free framework for scalable, robust, and reference-based cell-cell communication analysis in single cell transcriptomics studies.
  19. CRISPR screens in human neural organoids and assembloids.
  1. Nat Methods. 2025 Dec 15.
    Systematic scRNA-seq screens profile neural organoid response to morphogens.
    Fátima Sanchís-Calleja, Nadezhda Azbukina, Akanksha Jain, Zhisong He, Ryoko Okamoto, Charlotte Rusimbi, Pedro Rifes, Gaurav Singh Rathore, Malgorzata Santel, Jasper Janssens, Makiko Seimiya, Benedikt Eisinger, Jonas Simon Fleck, Agnete Kirkeby, J Gray Camp, Barbara Treutlein.
      Morphogens direct neuroepithelial fates toward discrete regional identities in vivo. Neural organoids provide models for studying neural regionalization through morphogen exposure; however, we lack a comprehensive survey of how the developing human neuroepithelium responds to morphogen cues. Here we produce a detailed survey of morphogen-induced effects on the regional specification of human neural organoids using multiplexed single-cell transcriptomic screens. We find that the timing, concentration and combination of morphogens strongly influence organoid cell-type and regional composition, and that cell line and neural induction method impact the response to a given morphogen condition. We apply concentration gradients in microfluidic chips or increasing static concentrations in multi-well plates and observe different patterning dynamics in each scenario. Altogether, we provide a detailed resource on neural lineage specification that, in combination with deep learning models, can enable the prediction of differentiation outcomes in human stem-cell-based systems.
    DOI:  https://doi.org/10.1038/s41592-025-02927-5
  2. Nat Methods. 2025 Dec 15.
    Carta offers a computational approach to inference of differentiation maps from cell lineages.
      
    DOI:  https://doi.org/10.1038/s41592-025-02904-y
  3. MedComm (2020). 2025 Dec;6(12): e70541
    Tumor Cell Plasticity in Cancer: Signaling Pathways and Pharmaceutical Interventions.
    Shangwei Sun, Yunwei Sun, Ling Lan, Siyuan Luan, Jin Zhou, Jiehui Deng, Yong Yuan, Zhong Wu.
      Cellular plasticity, the ability of cells to dynamically alter their phenotypes, is a key driver of tumor evolution. This process is a hallmark of cancer which enables the acquisition of malignant traits, leading to metastasis, progression, and therapy resistance. It is governed by cell-intrinsic factors, such as genomic instability and epigenetic reprogramming, and extrinsic stimuli from the tumor microenvironment. However, a unified framework is still needed to position plasticity as the central process that links these drivers to diverse cancer hallmarks. In this review, we first explore how plasticity enables key steps of tumor evolution, including tumorigenesis, metastasis driven by epithelial-mesenchymal plasticity (EMP), therapy resistance, and cancer stem cell (CSC) dynamics. We then summarize the intrinsic and extrinsic mechanisms that govern this adaptability. Finally, we discuss clinical advances in monitoring and targeting plasticity and highlight how new spatiotemporal technologies can address current research challenges. This review provides a framework positioning cellular plasticity as a central mechanism in cancer evolution, connecting its fundamental drivers to clinical translation. By synthesizing the latest advances, we offer perspectives for developing therapies that integrate prediction, monitoring, and targeting of plasticity to proactively guide cancer evolution toward manageable outcomes.
    Keywords:  differentiation therapy; epigenetic reprogramming; spatiotemporal omics; therapy resistance; tumor cell plasticity; tumor evolution; tumor microenvironment
    DOI:  https://doi.org/10.1002/mco2.70541
  4. bioRxiv. 2025 Dec 11. pii: 2025.12.08.693064. [Epub ahead of print]
    Building dynamical models of multi-step state transitions from single cell gene expression trajectories.
    Yukai You, Cristian Caranica, Mingyang Lu.
      Multi-step cell state transitions often occur in biological processes, such as cell differentiation and disease progression, yet the regulatory mechanisms governing these transitions remain unclear. Here, we introduce NetDes, a computational method that integrates top-down and bottom-up systems biology to infer core transcription factor regulatory networks and build ODE-based dynamical models from single-cell gene expression trajectories. We demonstrate that NetDes predicts regulatory interactions and reproduces gene expression dynamics through benchmarking using in-silico time trajectories with decoys, tests on gene circuit simulations of embryonic phenotypic switching, and application to time-series scRNA-seq data from human iPSC differentiation. Compared to existing approaches, NetDes has the advantage of capturing sequential state transitions within a single dynamical model. Network simulations and coarse-graining further elucidate the regulatory roles of genes and their combinations in driving these transitions. Our approach provides a generalizable framework for mechanistic modeling of gene regulation in complex cell state transitions.
    DOI:  https://doi.org/10.64898/2025.12.08.693064
  5. Gut. 2025 Dec 18. pii: gutjnl-2024-332243. [Epub ahead of print]
    Secondary bile acid production by gut bacteria promotes Western diet-associated colorectal cancer.
    Annika Osswald, Esther Wortmann, David Wylensek, Stephanie Kuhls, Olivia I Coleman, Kenneth Peuker, Anne Strigli, Quinten R Ducarmon, Martin Larralde, Wei Liang, Nicole S Treichel, Fabian Schumacher, Colin Volet, Silke Matysik, Karin Kleigrewe, Michael Gigl, Sascha Rohn, Chun-Jun Guo, Burkhard Kleuser, Gerhard Liebisch, Angelika Schnieke, Jason M Ridlon, Rizlan Bernier-Latmani, Georg Zeller, Sebastian Zeissig, Dirk Haller, Krzysztof Flisikowski, Thomas Clavel, Soeren Ocvirk.
       BACKGROUND: Western diet and associated production of secondary bile acids (BAs) have been linked to the development of sporadic colorectal cancer (CRC). Despite observational studies showing that secondary BAs produced by 7α-dehydroxylating (7αDH+) gut bacteria are increased in CRC, a causal proof of their tumour-promoting effects is lacking.
    OBJECTIVE: Investigate the causal role of BAs produced by 7αDH+ gut bacteria in CRC.
    DESIGN: We performed feeding studies in a porcine model of CRC combined with multi-omics analyses and gnotobiotic mouse models colonised with 7αDH+ bacteria or a genetically modified strain to demonstrate causality.
    RESULTS: Western diet exacerbated the CRC phenotype in APC 1311/+ pigs. This was accompanied by increased levels of the secondary BA deoxycholic acid (DCA) and higher colonic epithelial cell proliferation. The latter was counteracted by the BA-scavenging drug colestyramine. Metagenomic analysis across multiple human cohorts revealed higher occurrence of bai (BA inducible) operons from Clostridium scindens and close relatives in faeces of patients with CRC. Addition of these specific 7αDH+ bacteria (C. scindens/Extibacter muris) to defined communities of gut bacteria led to DCA production and increased colon tumour burden in mouse models of chemically or genetically induced CRC. A mutant strain of Faecalicatena contorta lacking 7αDH caused fewer colonic tumours in azoxymethane/dextran sodium sulfate treated mice and triggered less epithelial cell proliferation in human colon organoids compared with wild-type F. contorta.
    CONCLUSION: This work provides functional evidence for the causal role of secondary BAs produced by gut bacteria through 7αDH in CRC under adverse dietary conditions, opening avenues for future preventive strategies.
    Keywords:  BILE ACID; BILE ACID METABOLISM; COLORECTAL CANCER; DIETARY - COLON CANCER; MICROBIOME
    DOI:  https://doi.org/10.1136/gutjnl-2024-332243
  6. Nat Methods. 2025 Dec 16.
    Dissecting how morphogens shape cell fates in human neural organoids.
      
    DOI:  https://doi.org/10.1038/s41592-025-02959-x
  7. bioRxiv. 2025 Dec 12. pii: 2025.12.10.692786. [Epub ahead of print]
    Regulatory element modules as universal features for single-cell chromatin analysis.
    Chrysania Lim, Javen Tan Yih Ruay, Tim Stuart.
      Single-cell chromatin accessibility data provide important insights into the activity of DNA regulatory elements in health and disease. However, the analysis of these data is made challenging by the lack of a common set of features for use in downstream analysis. This results in individual studies quantifying dataset-specific peak regions that cannot be directly compared to other studies. To address this challenge, we developed a comprehensive set of DNA regulatory element modules (REMO) for the human genome. Here we show how REMO can be applied to single-cell chromatin data to better separate cell states in a low-dimensional space compared to peak matrix quantification, greatly improve the scalability of dimension reduction steps, and enable automated annotation of cell types. This is accompanied by new memory-efficient and scalable software for the quantification of single-cell chromatin accessibility data.
    Abstract Figure:
    DOI:  https://doi.org/10.64898/2025.12.10.692786
  8. Nat Comput Sci. 2025 Dec 16.
    Harnessing LLMs to decode genetic perturbations.
    Zijing Gao, Rui Jiang.
      
    DOI:  https://doi.org/10.1038/s43588-025-00910-w
  9. Exp Cell Res. 2025 Dec 15. pii: S0014-4827(25)00467-7. [Epub ahead of print] 114867
    Metabolic Adaptation in Colorectal Cancer Microenvironment: Focus on Cancer-Associated Fibroblasts (CAFs) and Tumor-Associated Macrophages (TAMs).
    Chou-Yi Hsu, Amr Ali Mohamed Abdelgawwad El-Sehrawy, Mirza R Baig, Zahraa Khudhair, Saidmurodkhon Murtazaev, Pareshkumar N Patel, Subbulakshmi Ganesan, Vimal Arora, Sandeep Kumar Shukla, Priya Priyadarshini Nayak.
      Metabolic reprogramming within the tumor microenvironment (TME) is a critical driver of colorectal cancer (CRC) progression, influencing tumor growth, immune evasion, and metastatic dissemination. Cancer-associated fibroblasts (CAFs) undergo adaptive shifts toward aerobic glycolysis, a process often termed the "reverse Warburg effect," producing high levels of lactate and pyruvate that are shuttled to adjacent CRC cells to fuel oxidative phosphorylation and anabolic biosynthesis. CAFs additionally secrete cytokines and growth factors, including TGF-β, IL-6, and VEGF, which integrate metabolic and signaling networks to stimulate epithelial-mesenchymal transition (EMT), angiogenesis, and metastatic potential. Similarly, tumor-associated macrophages (TAMs) exhibit remarkable metabolic plasticity that correlates with their functional heterogeneity. Beyond the classical M1/M2 dichotomy, TAM subsets display differential reliance on oxidative phosphorylation, fatty acid oxidation, or glycolysis depending on local oxygen and nutrient availability. M2-like TAMs, for example, preferentially use oxidative phosphorylation and fatty acid metabolism to sustain survival in hypoxic niches while secreting immunosuppressive metabolites such as arginase, polyamines, and lactate, which inhibit cytotoxic T-cell function. Crosstalk between CAFs and TAMs amplifies these metabolic adaptations: CAF-derived lactate promotes M2 polarization, while TAMs enhance glycolysis and biosynthetic activity in tumor cells. This study aims to systematically investigate the metabolic reprogramming of CAFs and TAMs within the CRC tumor microenvironment. Specifically, we seek to characterize the metabolic adaptations and heterogeneity of these stromal populations, elucidate their reciprocal interactions with tumor cells, and identify potential metabolic vulnerabilities that can be therapeutically targeted to disrupt tumor growth, immune evasion, and metastatic progression.
    Keywords:  CAF; Colorectal cancer; Immune cell; TAM; TME
    DOI:  https://doi.org/10.1016/j.yexcr.2025.114867
  10. bioRxiv. 2025 Nov 28. pii: 2025.11.26.690796. [Epub ahead of print]
    LARIS enables accurate and efficient ligand and receptor interaction analysis in spatial transcriptomics.
    Min Dai, Tivadar Török, Dawei Sun, Vallari Shende, Grace Wang, Yuesang Lin, Sherry Jingjing Wu, Alyssa Rukshin, Gord Fishell, Fei Chen.
      Advances in spatially resolved transcriptomics provide unprecedented opportunities to characterise intercellular communication pathways. However, robust and computationally efficient incorporation of spatial information into intercellular communication inference remains challenging. Here, we present LARIS ( L igand A nd R eceptor Interaction analysis in S patial transcriptomics), an accurate and scalable method that identifies cell type-specific and spatially restricted ligand-receptor (LR) interactions at single-cell or bead resolution. LARIS is compatible with all spatial transcriptomic technologies and quantifies specificity, infers sender-receiver directionality, and detects how differential interactions vary across time and space. To compare LARIS with existing methods, we established a simulation framework to generate ground truth of LR interactions with defined tissue architecture and gene expression patterns. LARIS demonstrates superior performances over other methods in accuracy and scalability. We further applied LARIS to human tonsil and developing mouse cortex spatial transcriptomics datasets collected from various spatial techniques. This uncovered the signalling mechanisms shaping tissue organisation and their changes over time. LARIS reveals cell type-, niche-, and condition-specific signalling and scales to hundreds of thousands of cells in minutes. This provides an efficient and direct method for discovering the molecular interplay between apposed cells across development.
    DOI:  https://doi.org/10.1101/2025.11.26.690796
  11. Hum Genomics. 2025 Dec 15. 19(1): 146
    Early mutational events and clonal dynamics in normal crypts: implications for colorectal tumorigenesis.
    Charlie Marvalim, Dedrick Kok Hong Chan.
      
    Keywords:  Cell-autonomous effects; Clonal evolution; Colorectal cancer; Intratumoral heterogeneity; Microenvironmental interactions; Somatic driver mutations; Tumor-initiating events
    DOI:  https://doi.org/10.1186/s40246-025-00889-5
  12. Nat Genet. 2025 Dec 18.
    Nucleophosmin supports WNT-driven hyperproliferation and tumor initiation.
    Georgios Kanellos, Chiara Giacomelli, Alexander Raven, Nikola Vlahov, Hu Jin, Pauline Herviou, Sudhir B Malla, Nadia Nasreddin, Patricia P Centeno, Constantinos Alexandrou, Kathryn Gilroy, Rachel L Baird, Kathryn Pennel, June Munro, Joseph A Waldron, Holly Hall, Leah Officer-Jones, Sheila Bryson, Douglas Strathdee, Sergio Lilla, Sara Zanivan, Vivienne Morrison, Colin Nixon, Rachel A Ridgway, Crispin Miller, John R P Knight, Andrew D Campbell, Philip D Dunne, John Le Quesne, Joanne Edwards, Peter J Park, Martin Bushell, Owen J Sansom.
      Nucleophosmin (NPM1), a nucleolar protein frequently mutated in hematopoietic malignancies, is overexpressed in several solid tumors with poorly understood functional roles. Here, we demonstrate that Npm1 is upregulated after APC loss in WNT-responsive tissues and supports WNT-driven intestinal and liver tumorigenesis. Mechanistically, NPM1 loss induces ribosome pausing and accumulation at the 5'-end of coding sequences, triggering a protein synthesis stress response and p53 activation, which mediate this antitumorigenic effect. Collectively, our data identify NPM1 as a critical WNT effector that sustains WNT-driven hyperproliferation and tumorigenesis by attenuating the integrated stress response and p53 activation. Notably, NPM1 expression correlates with elevated WNT signaling and proliferation in human colorectal cancer (CRC), while CRCs harboring NPM1 deletions exhibit preferential TP53 inactivation, underscoring the clinical relevance of our findings. Being dispensable for adult epithelial homeostasis, NPM1 represents a promising therapeutic target in p53-proficient WNT-driven tumors, including treatment-refractory KRAS-mutant CRC, and hepatic cancers.
    DOI:  https://doi.org/10.1038/s41588-025-02408-7
  13. Science. 2025 Dec 18. eady7209
    Multistep genomics on single cells and live cultures in subnanoliter capsules.
    Ignas Mazelis, Haoxiang Sun, Arpita Kulkarni, Theresa L Torre, Allon M Klein.
      Single-cell sequencing methods uncover natural and induced variation between cells. Many functional genomic methods, however, require multiple steps that cannot yet be scaled to high throughput, including assays on living cells. Here we develop capsules with amphiphilic gel envelopes (CAGEs), which selectively retain cells and large analytes while being freely accessible to media, enzymes and reagents. Capsules enable high-throughput multistep assays combining live-cell culture with genome-wide readouts. We establish methods for barcoding CAGE DNA libraries, and apply them to measure persistence of gene expression programs in cells by capturing the transcriptomes of tens of thousands of expanding clones in CAGEs. The compatibility of CAGEs with diverse enzymatic reactions will facilitate the expansion of the current repertoire of single-cell, high-throughput measurements and their extension to live-cell assays.
    DOI:  https://doi.org/10.1126/science.ady7209
  14. Nat Methods. 2025 Dec 18.
    Methods to analyze cell migration data: fundamentals and practical guidelines.
    Pei-Hsun Wu, Jude M Phillip, Wenxuan Du, Andre Forjaz, Praful R Nair, Denis Wirtz.
      Cell migration assays provide invaluable insights into fundamental biological processes. In a companion Review, we describe commercial and custom in vitro and in vivo assays to measure cell migration and provide guidelines on how to select the most appropriate assay for a given biological question. Here, we describe the fundamental principles of how to compute-from the raw data generated by these assays-quantitative cell migration parameters that help determine the biophysical nature of the cell migration, such as cell speed, mean-squared displacement, diffusivity, persistence, speed and anisotropy, and how to quantify cell heterogeneity, with practical guidance. We also describe new imaging and computational technologies, including AI-based methods, which have helped establish fast, robust and accurate tracking of cells and quantification of cell migration. Taken together, these Reviews offer practical guidance for cell migration assays from conception to analysis.
    DOI:  https://doi.org/10.1038/s41592-025-02935-5
  15. FEBS Lett. 2025 Dec 16.
    Mapping human neurodevelopment-Brain organoids meet lineage tracing.
    Carla Liaci, Giorgia Quadrato.
      Brain organoids, as self-organizing three-dimensional in vitro systems, offer a significant advantage over traditional models by enabling longitudinal analysis of developing human tissues. Their dynamic nature allows for the investigation of biological processes across time, a crucial 'fourth dimension' often lacking in highly reductionist in vitro models and essential to comprehensively study evolutionary and pathogenetic processes. Furthermore, the inherent genetic amenability of organoids facilitates the integration of advanced technologies, creating novel opportunities to exploit synthetic biology tools. In this regard, novel lineage tracing systems that integrate omics technologies are now dissecting complex human biological processes with unprecedented resolution. This review presents the current state of the art regarding the application of brain organoids for understanding human developmental processes related to cell lineage and temporal progression, highlighting studies that have developed dedicated lineage tracing tools. We further discuss the limitations inherent in current technologies and the potential improvements required to advance their fidelity, scalability, and translational relevance in modeling human brain development and disease.
    Keywords:  brain organoids; human brain development; lineage tracing
    DOI:  https://doi.org/10.1002/1873-3468.70250
  16. Nat Methods. 2025 Dec 18.
    Selecting the optimal cell migration assay: fundamentals and practical guidelines.
    Wenxuan Du, Praful R Nair, Andre Forjaz, Jude M Phillip, Pei-Hsun Wu, Denis Wirtz.
      Cell migration is a key cellular process that drives major developmental programs. To mimic and mechanistically understand cell migration in these different contexts, different assays have been developed. However, owing to the lack of practical guidelines, these different cell migration assays are often used interchangeably. This and the inherent dynamic nature of cell migration, which often requires sophisticated live-cell microscopy, may have caused cell migration to be notably less well understood than equally important cell functions, such as cell differentiation or proliferation. In this Review, we describe commonly used custom and commercial in vitro and in vivo cell migration assays and provide a comprehensive practical guide and decision tree outlining how to choose and implement an assay that best suits the biological question at hand. We hope this guidance spurs biological insights into this complex process and encourages future methods development.
    DOI:  https://doi.org/10.1038/s41592-025-02890-1
  17. Cancer Discov. 2025 Nov 26. OF1
    Tumor-infiltrating Bacteria Induce Quiescence and Therapy Resistance.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2025-102
  18. Nat Commun. 2025 Dec 13.
    FastCCC: a permutation-free framework for scalable, robust, and reference-based cell-cell communication analysis in single cell transcriptomics studies.
    Siyu Hou, Wenjing Ma, Xiang Zhou.
      Detecting cell-cell communications (CCCs) in single-cell transcriptomics studies is fundamental for understanding the function of multicellular organisms. Here, we introduce FastCCC, a permutation-free framework that enables scalable, robust, and reference-based analysis for identifying critical CCCs and uncovering biological insights. FastCCC relies on fast Fourier transformation-based convolution to compute p-values analytically without permutations, introduces a modular algebraic operation framework to capture a broad spectrum of CCC patterns, and can leverage atlas-scale single cell references to enhance CCC analysis on user-collected datasets. To support routine reference-based CCC analysis, we constructed the first human CCC reference panel, encompassing 19 distinct tissue types, over 450 unique cell types, and approximately 16 million cells. We demonstrate the advantages of FastCCC across multiple datasets, most of which exceed the analytical capabilities of existing CCC methods. In real datasets, FastCCC reliably captures biologically meaningful CCCs, even in highly complex tissue environments, including differential interactions between endothelial and immune cells linked to COVID-19 severity, dynamic communications in thymic tissue during T-cell development, as well as distinct interactions in reference-based CCC analysis.
    DOI:  https://doi.org/10.1038/s41467-025-66272-z
  19. Nat Protoc. 2025 Dec 19.
    CRISPR screens in human neural organoids and assembloids.
    Xiangling Meng, Noah Reis, Michael C Bassik, Sergiu P Pașca.
      Studying the molecular mechanisms underlying the assembly of the human nervous system remains a significant challenge. The ability to generate neural cells from pluripotent stem cells, combined with advanced genome-editing techniques, provides unprecedented opportunities to uncover the biology of human neurodevelopment and disease. Organoids and assembloids enable the in vitro modeling of previously inaccessible developmental processes, such as the specification and migration of human neurons, including the integration of cortical interneurons from the ventral into the dorsal forebrain. Here, we present a detailed protocol that combines pooled CRISPR-Cas9 screening with neural organoid and assembloid models and illustrate how it can be applied to map hundreds of disease genes onto cellular pathways and specific aspects of human neural development. Our protocol outlines key steps, from planning and optimizing genetic perturbations to designing readouts for neuronal generation and migration, conducting the screening and validating candidate genes. The screening experiments take ~3 months to complete and require expertise in stem cell culture and neural differentiation, genetic engineering of human induced pluripotent stem cell lines, fluorescence-activated cell sorting and next-generation sequencing and analyses. The integration of genetic screening and human cellular models constitutes a powerful platform for investigating the mechanisms of human brain development and disease, paving the way for the discovery of novel therapeutics.
    DOI:  https://doi.org/10.1038/s41596-025-01299-6
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