bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–07–13
thirteen papers selected by
Xiao Qin, University of Oxford
  1. Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.
  2. Systematic assessment of microenvironment-dependent transcriptional patterns and intercellular communication.
  3. Mathematical modelling of cancer cell evolution and plasticity.
  4. Spatial joint profiling of DNA methylome and transcriptome in mammalian tissues.
  5. A Framework for Advancing Colorectal Cancer Screening, Follow-Up, and Care Delivery for All.
  6. Modelling the ageing dependence of cancer evolutionary trajectories.
  7. Automated cell annotation and classification on histopathology for spatial biomarker discovery.
  8. The tumor microenvironment across four dimensions: assessing space and time in cancer biology.
  9. Stem-Cell Niches in Health and Disease: Microenvironmental Determinants of Regeneration and Pathology.
  10. Pericyte phenotype switching in cancer.
  11. Decoding the genomic landscape of early-onset colorectal cancer: the next chapter in precision oncology.
  12. Benchmarking single-cell multi-modal data integrations.
  13. A rapid and robust protocol for generating loss-of-function alleles in pluripotent stem cells.
  1. Gastroenterology. 2025 Jul 07. pii: S0016-5085(25)05732-4. [Epub ahead of print]
    Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.
    Pornlada Likasitwatanakul, Zhixin Li, Paul Doan, Sandor Spisak, Akhouri Kishore Raghawan, Qi Liu, Priscilla Liow, Sunwoo Lee, David Chen, Pratyusha Bala, Pranshu Sahgal, Daulet Aitymbayev, Jennifer S Thalappillil, Malvina Papanastasiou, William Hawkins, Steven A Carr, Haeseong Park, James M Cleary, Jun Qi, Nilay S Sethi.
       BACKGROUND AND AIMS: Aberrant epigenetic programs that suppress differentiation and enhance plasticity drive colorectal cancer (CRC), yet the molecular determinants underlying these processes remain elusive. We aimed to identify and characterize epigenetic regulators of CRC differentiation, uncovering mechanisms that reprogram cancer cell states.
    METHODS: A small molecule library targeting epigenetic regulators was screened using an endogenous dual reporter system. We evaluated lead compounds in mouse and human CRC models via histopathology, cellular assays, epigenetic studies, mass-spectrometry-based histone modification profiling, and single cell RNA-sequencing. Integrative analyses of drug-induced chromatin dynamics, gene expression, target engagement, and histone marks elucidated molecular mechanisms. Focused genetic screens were conducted to identify regulators of HDAC1/2-mediated differentiation.
    RESULTS: We found that inhibition of histone deacetylase (HDAC) 1/2 catalytic domain promotes CRC differentiation and suppresses tumor growth. Unbiased profiling of histone modifications identified H3K27ac and H3K9ac as critical regulatory marks, with genome-wide analyses demonstrating their enrichment at HDAC1/2-bound regions associated with open chromatin and upregulated differentiation genes. Disrupting H3K27ac by targeted degradation of acetyltransferase EP300 reversed the differentiation phenotype induced by HDAC1/2 inhibition in a patient-derived CRC organoid. Genetic screens revealed that DAPK3 contributes to H3K27ac-mediated CRC differentiation induced by HDAC1/2 inhibition.
    CONCLUSIONS: Our findings establish histone acetylation as a chemically targetable mechanism governing CRC cell fate and demonstrate that epigenetic reprogramming can be leveraged as a therapeutic strategy. By identifying HDAC1/2 inhibition as a driver of differentiation and revealing H3K27ac as a key regulatory mark, this study provides a framework for targeting chromatin-modifying enzymes to counteract CRC plasticity and improve treatment outcomes.
    Keywords:  colorectal cancer; epigenetic regulation; intestinal differentiation; stem cell
    DOI:  https://doi.org/10.1053/j.gastro.2025.07.003
  2. Genome Biol. 2025 Jul 06. 26(1): 193
    Systematic assessment of microenvironment-dependent transcriptional patterns and intercellular communication.
    Elena Pareja-Lorente, Patrick Aloy.
       BACKGROUND: Understanding cell-cell communication and its dependence on spatial organization is critical for unraveling tissue complexity and organ function, and it has been demonstrated that cells are influenced by their microenvironment and neighboring cells, affecting their gene expression and intercellular interactions. This study integrates single-cell RNA sequencing (scRNA-seq) with spatial transcriptomics (ST) to systematically assess how spatial niches influence gene expression and intercellular communication.
    RESULTS: Using breast cancer, brain cortex, and heart datasets, our analyses reveal limited global transcriptional changes in cells depending on their spatial microenvironment, with differential gene expression observed in half of the samples explored. Moreover, cell-cell communication predictions, derived from ligand-receptor pairs, exhibit minimal correlation with spatial colocalization of cell types.
    CONCLUSIONS: Overall, our study underscores the limitations of using scRNA-seq data to capture niche-specific molecular interactions, even when spatial information is leveraged, and it highlights the need for novel strategies to refine our understanding of intercellular communication dynamics at the molecular level.
    DOI:  https://doi.org/10.1186/s13059-025-03677-5
  3. Curr Opin Cell Biol. 2025 Jul 09. pii: S0955-0674(25)00096-1. [Epub ahead of print]95 102558
    Mathematical modelling of cancer cell evolution and plasticity.
    Chloé Colson, Frederick Jh Whiting, Ann-Marie Baker, Trevor A Graham.
      In this review, we argue that mathematical modelling is an essential tool for understanding cancer cell evolution and phenotypic plasticity. We show that mathematical models enable us to reconstruct time-dependent tumour evolutionary dynamics from temporally-restricted biological data. In their ability to capture complex biological processes, they also serve as a means for in silico experimentation. In particular, they allow us to investigate different biological hypotheses and generate experimentally-testable predictions about underlying mechanisms of phenotype evolution and treatment resistance. Finally, mathematical models can reveal which biological data is informative, and, in combination with our understanding of which biological hypotheses need to be tested, they can guide experimental and clinical trial design.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102558
  4. bioRxiv. 2025 Jul 04. pii: 2025.07.01.662607. [Epub ahead of print]
    Spatial joint profiling of DNA methylome and transcriptome in mammalian tissues.
    Chin Nien Lee, Hongxiang Fu, Angelysia Cardilla, Wanding Zhou, Yanxiang Deng.
      The spatial resolution of omics dynamics is fundamental to understanding tissue biology. Spatial profiling of DNA methylation, which is a canonical epigenetic mark extensively implicated in transcriptional regulation, remains an unmet demand. Here, we introduce a method for whole genome spatial co-profiling of DNA methylation and transcriptome of the same tissue section at near single-cell resolution. Applying this technology to mouse embryogenesis and postnatal brain resulted in rich DNA-RNA bimodal tissue maps. These maps revealed the spatial context of known methylation biology and its interplay with gene expression. The two modalities' concordance and distinction in spatial patterns highlighted a synergistic molecular definition of cell identity in spatial programming of mammalian development and brain function. By integrating spatial maps of mouse embryos at two different developmental stages, we reconstructed the dynamics of both epigenome and transcriptome underlying mammalian embryogenesis, revealing details in sequence, cell type, and region-specific methylation-mediated transcriptional regulation. This method extends the scope of spatial omics to DNA cytosine methylation for a more comprehensive understanding of tissue biology over development and disease.
    DOI:  https://doi.org/10.1101/2025.07.01.662607
  5. Health Educ Behav. 2025 Jul 11. 10901981251346803
    A Framework for Advancing Colorectal Cancer Screening, Follow-Up, and Care Delivery for All.
    Sarah Kobrin, Sujha Subramanian, Sonja Hoover, Sharon McCarthy, Sheila F Castañeda, Shiraz I Mishra.
      Increasing colorectal cancer (CRC) screening requires delivery and adaptation of evidence-based and theory-guided interventions. The Accelerating Colorectal Cancer Screening and Follow-up through Implementation Science (ACCSIS) consortium is funded by the National Cancer Institute, with a primary goal of increasing the availability and use of approaches to CRC prevention and control, from screening through follow-up testing, diagnosis, and referral to care. In this article, we present a framework for improving CRC, follow-up, and referral to care among populations that have low CRC screening rates. We used a multistep, consensus- and data-driven approach to develop the ACCSIS framework. Eight collaborating Research Projects of the ACCSIS consortium evaluated the draft; they provided feedback in relation to their study designs, settings, populations, and methods. They also used evaluation results to refine the framework until they reached consensus. The current framework reflects common elements, expected intervention and screening outcomes, and is intended to contribute to future ACCSIS analyses and others' intervention and research plans. The framework recognizes the iterative nature of CRC screening programs and emphasizes multiple levels of influence-from baseline factors affecting selection of intervention components through measurement of process, screening, and implementation outcomes. Future researchers and practitioners can adapt the ACCSIS framework to advance CRC screening and to improve other cancer prevention and control research and practices that have created and perpetuated health disparities.
    Keywords:  colorectal cancer screening; framework; practice
    DOI:  https://doi.org/10.1177/10901981251346803
  6. Nat Rev Cancer. 2025 Jul 10.
    Modelling the ageing dependence of cancer evolutionary trajectories.
    Curtis J Henry, James DeGregori.
      Ageing is the single most important prognostic factor for cancer development. Despite this knowledge, experimental models of cancer have historically omitted incorporating the impact of age on cancer initiation, progression and treatment outcomes. Ageing interacts with other lifestyle factors, including cigarette smoking, obesity and physical activity, but these intersections are rarely studied in experimental models. Given that cancer-related mortality rates increase with age, there is a growing emphasis on modelling ageing-associated mutational and microenvironmental changes in cancer research. In this Review, we provide guidance on the technological advancements and experimental strategies that have increased our ability to model how ageing impacts various stages of cancer evolution, from mutation-driven clonal expansions, to pre-malignant lesions, and then to progression to more malignant phenotypes and metastasis, and responses to therapies. We discuss the benefits and limitations of methods and models used. The wider adoption of age-appropriate models of cancer will enable the development of improved approaches for the detection, prevention and therapeutic intervention of human cancers.
    DOI:  https://doi.org/10.1038/s41568-025-00838-3
  7. Nat Commun. 2025 Jul 07. 16(1): 6240
    Automated cell annotation and classification on histopathology for spatial biomarker discovery.
    Zhe Li, Seyed Hossein Mirjahanmardi, Rasoul Sali, Feyisope Eweje, Matthew Gopaulchan, Leon Kloker, Xiaoming Zhang, Guoxin Li, Yuming Jiang, Ruijiang Li.
      Histopathology with hematoxylin and eosin (H&E) staining is routinely employed for clinical diagnoses. Single-cell analysis of histopathology provides a powerful tool for understanding the intricate cellular interactions underlying disease progression and therapeutic response. However, existing efforts are hampered by inefficient and error-prone human annotations. Here, we present an experimental and computational approach for automated cell annotation and classification on H&E-stained images. Instead of human annotations, we use multiplexed immunofluorescence (mIF) to define cell types based on cell lineage protein markers. By co-registering H&E images with mIF of the same tissue section at the single-cell level, we create a dataset of 1,127,252 cells with high-quality annotations on tissue microarray cores. A deep learning model combining self-supervised learning with domain adaptation is trained to classify four cell types on H&E images with an overall accuracy of 86%-89%, and the cell classification model is applicable to whole slide images. Further, we show that spatial interactions among specific immune cells in the tumor microenvironment are linked to patient survival and response to immune checkpoint inhibitors. Our work provides a scalable approach for single-cell analysis of standard histopathology and may enable discovery of novel spatial biomarkers for precision oncology.
    DOI:  https://doi.org/10.1038/s41467-025-61349-1
  8. Front Immunol. 2025 ;16 1554114
    The tumor microenvironment across four dimensions: assessing space and time in cancer biology.
    Christina R Larson, Ayushi Mandloi, Satwik Acharyya, Julienne L Carstens.
      The tumor microenvironment is heterogeneous, structurally complex, and continually evolving, making it difficult to fully capture. Common dissociative techniques thoroughly characterize the heterogeneity of cellular populations but lack structural context. The recent boom in spatial analyses has exponentially accelerated our understanding of the structural complexity of these cellular populations. However, to understand the dynamics of cancer pathogenesis, we must assess this heterogeneity across space and time. In this review, we provide an overview of current dissociative, spatial, and temporal analysis strategies in addition to existing and prospective spatiotemporal techniques to illustrate how understanding the tumor microenvironment, focusing on dynamic immune-cancer cell interactions, across four dimensions will advance cancer research and its diagnostic and therapeutic applications.
    Keywords:  intravital imaging; spatial omics; spatiotemporal; temporal analysis; tumor evolution; tumor immune microenvironment; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1554114
  9. Cells. 2025 Jun 26. pii: 981. [Epub ahead of print]14(13):
    Stem-Cell Niches in Health and Disease: Microenvironmental Determinants of Regeneration and Pathology.
    Boris Yushkov, Valerii Chereshnev, Elena Korneva, Victoria Yushkova, Alexey Sarapultsev.
      Stem-cell behavior is governed not solely by intrinsic genetic programs but by highly specialized microenvironments-or niches-that integrate structural, biochemical, and mechanical cues to regulate quiescence, self-renewal, and differentiation. This review traces the evolution of stem-cell niche biology from foundational embryological discoveries to its current role as a central determinant in tissue regeneration and disease. We describe the cellular and extracellular matrix architectures that define adult stem-cell niches across diverse organs and dissect conserved signaling axes-including Wnt, BMP, and Notch-that orchestrate lineage commitment. Emphasis is placed on how aging, inflammation, fibrosis, and metabolic stress disrupt niche function, converting supportive environments into autonomous drivers of pathology. We then examine emerging therapeutic strategies that shift the regenerative paradigm from a stem-cell-centric to a niche-centric model. These include stromal targeting (e.g., FAP inhibition), which are engineered scaffolds that replicate native niche mechanics, extracellular vesicles that deliver paracrine cues, and composite constructs that preserve endogenous cell-matrix interactions. Particular attention is given to cardiac, hematopoietic, reproductive, and neurogenic niches, where clinical failures often reflect niche misalignment rather than intrinsic stem-cell deficits. We argue that successful regenerative interventions must treat stem cells and their microenvironment as an inseparable therapeutic unit. Future advances will depend on high-resolution niche mapping, mechanobiologically informed scaffold design, and niche-targeted clinical trials. Re-programming pathological niches may unlock regenerative outcomes that surpass classical cell therapies, marking a new era of microenvironmentally integrated medicine.
    Keywords:  Wnt signaling; angiogenesis; extracellular matrix; extracellular vesicles; hematopoiesis; microenvironment; regenerative medicine; self-renewal; stem-cell niche; tissue engineering
    DOI:  https://doi.org/10.3390/cells14130981
  10. Trends Cancer. 2025 Jul 07. pii: S2405-8033(25)00147-5. [Epub ahead of print]
    Pericyte phenotype switching in cancer.
    Bo He, Ruth Ganss.
      Pericytes play an important physiological role as guardians of vascular integrity. In cancer, however, pericytes undergo profound phenotypic changes which foster tumor progression. Emerging transcriptomics and functional data provide evidence for a shift from quiescent to highly proliferating, matrix-secreting pericytes which destabilize the vasculature and create immune deserts. However, due to their inherent plasticity, proliferative tumor pericytes can be 'coerced' to switch back into a more quiescent and contractile state, a process which underpins durable tumor vessel normalization. Therapeutically, pericyte phenotype switching can be induced by targeting oncogenic, metabolic, or microtubule signaling pathways which induce Rho kinase activity. Thus, harnessing pericyte plasticity provides unique opportunities to synergize targeted anticancer therapies with immunotherapy.
    Keywords:  angiogenesis; blood vessel normalization; cancer; immunotherapy; pericytes
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.005
  11. Lancet Oncol. 2025 Jul 02. pii: S1470-2045(25)00285-2. [Epub ahead of print]
    Decoding the genomic landscape of early-onset colorectal cancer: the next chapter in precision oncology.
    Andreas Seeber.
      
    DOI:  https://doi.org/10.1016/S1470-2045(25)00285-2
  12. Nat Methods. 2025 Jul 10.
    Benchmarking single-cell multi-modal data integrations.
    Shaliu Fu, Shuguang Wang, Duanmiao Si, Gaoyang Li, Yawei Gao, Qi Liu.
      Recent advances have enabled the generation of both unpaired (separate profiling) and paired (simultaneous measurement) single-cell multi-modal datasets, driving rapid development of single-cell multi-modal integration tools. Nevertheless, there is a pressing need for a comprehensive benchmark to assess algorithms under varying integrated dataset types, integrated modalities, dataset sizes and data quality. Here we present a systematic benchmark for 40 single-cell multi-modal integration algorithms involving modalities of DNA, RNA, protein and spatial omics for paired, unpaired and mosaic datasets (a mixture of paired and unpaired datasets). We evaluated usability, accuracy and robustness to assist researchers in selecting suitable integration methods tailored to their datasets and applications. Our benchmark provides valuable guidance in the ever-evolving field of single-cell multi-omics.
    DOI:  https://doi.org/10.1038/s41592-025-02737-9
  13. STAR Protoc. 2025 Jul 04. pii: S2666-1667(25)00322-3. [Epub ahead of print]6(3): 103916
    A rapid and robust protocol for generating loss-of-function alleles in pluripotent stem cells.
    Erdene Baljinnyam, Laura Grisanti, Shalini Tattari, Chiara Pedicone, Bhavana Shewale, Nicole Dubois, Alison M Goate, William G Kerr, Samuele G Marro.
      The generation of loss-of-function alleles in human pluripotent stem cells (hPSCs) is used to interrogate gene function and validate reagents; however, identifying clones harboring true loss-of-function alleles remains inefficient. To address this, we present BOLT (barcoded oligos for loss-of-function targeting), a streamlined protocol that simplifies the screening process, facilitating rapid validation of loss-of-function mutations. We describe steps for designing editing tools, nucleofection, and clonal density plating. We then detail procedures for bridging PCR, isolating clones derived from a single hPSC, single-clone screening, and Sanger barcode detection. For complete details on the use and execution of this protocol, please refer to Matera et al.1.
    Keywords:  CRISPR; Cell Biology; Cell culture; Genomics; Molecular Biology; Sequencing; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.103916
This page is being maintained by Thomas Krichel. It was last updated on 2025‒07‒15 at 11:08.