bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–08–31
seventeen papers selected by
Xiao Qin, University of Oxford
  1. Transcriptomic Comparisons of Somatic and Cancer Stem Cells.
  2. Fibroblast Modulation of Stem Cell Lineage Infidelity and Metaplasia in Tissue Fibrosis.
  3. Single-cell multi-omics characterize colorectal tumors, adjacent healthy tissue and matched (tumor) organoids identifying CRC-unique features.
  4. Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings.
  5. Reverse control of biological networks to restore phenotype landscapes.
  6. The evolution of cancer and ageing: a history of constraint.
  7. Mechanical confinement governs phenotypic plasticity in melanoma.
  8. Single-cell omics sequencing technologies: the long-read generation.
  9. Systema: a framework for evaluating genetic perturbation response prediction beyond systematic variation.
  10. Imaging-based multimodal profiling of single cells with STAMP.
  11. Understanding cancer cell plasticity: EMT, respecialisation, and therapeutic opportunities.
  12. From gene lists to context drift.
  13. 3D collagen high-throughput screen identifies drugs that induce epithelial polarity and enhance chemotherapy response in colorectal cancer.
  14. Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer.
  15. Prospects for personalized cancer treatment in the era of single-cell sequencing.
  16. Challenges and proposed solutions to the adoption of cell free DNA in screening, detecting and prognosticating colorectal cancer.
  17. Shifts in cancer funding: An overview of terminated research grants at the national cancer institute.
  1. Biomedicines. 2025 Aug 21. pii: 2039. [Epub ahead of print]13(8):
    Transcriptomic Comparisons of Somatic and Cancer Stem Cells.
    Austin Drysch, Arun Ahuja, Dillan Prasad, Rishi Jain, Sharbel Romanos, Amr Alwakeal, Christopher Ahuja.
      Stem cells are essential for tissue maintenance, repair, and regeneration, yet their dysregulation gives rise to cancer stem cells (CSCs), which drive tumor progression, metastasis, and therapy resistance. Despite extensive research on stemness and oncogenesis, a critical gap remains in our understanding of how the transcriptomic landscapes of normal somatic stem cells (SSCs) diverge from those of CSCs to enable malignancy. This review synthesizes current knowledge of the key signaling pathways (Wnt, Notch, Hedgehog, TGF-β), transcription factors (Oct4, Sox2, Nanog, c-Myc, YAP/TAZ), and epigenetic mechanisms (chromatin remodeling, DNA methylation, microRNA regulation) that govern stemness in SSCs and are hijacked or dysregulated in CSCs. We highlight how context-specific modulation of these pathways distinguishes physiological regeneration from tumorigenesis. Importantly, we discuss the role of epithelial-mesenchymal transition (EMT), cellular plasticity, and microenvironmental cues in reprogramming and maintaining CSC phenotypes. By integrating transcriptomic and epigenetic insights across cancer biology and regenerative medicine, this review provides a framework for identifying vulnerabilities specific to CSCs while still preserving normal stem cell function. Understanding these distinctions is essential for the development of targeted therapies that minimize damage to healthy tissues and advance precision oncology.
    Keywords:  cancer stem cells; precision medicine; regenerative medicine; signaling pathways; somatic stem cells; stemness; transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.3390/biomedicines13082039
  2. Annu Rev Pathol. 2025 Aug 21.
    Fibroblast Modulation of Stem Cell Lineage Infidelity and Metaplasia in Tissue Fibrosis.
    Tsukasa Kadota, Tien Peng.
      Epithelial stem cells are segregated on the basis of region-specific identities during homeostasis. However, tissue perturbations can induce remarkable plasticity in stem cells to adopt lineage identities outside their anatomical compartments. This phenomenon has been termed lineage infidelity or metaplasia depending on the tissue, and the stem cell trajectory can determine regenerative outcomes relevant to many diseases, including fibrosis. While many studies have shed light on stem-cell intrinsic mechanisms that govern their ability to switch identities, much less is known about microenvironmental factors that alert stem cells and modify their lineage decisions. Fibroblasts are structural cells that provide the necessary scaffolding for stem cells in their native niche, but fibroblasts also sense external changes to the tissue environment to drive the tissue response. In this review, we explore the role of fibroblasts as a critical orchestrator of lineage plasticity that blurs compartmental identities to initiate proper repair or disease.
    DOI:  https://doi.org/10.1146/annurev-pathmechdis-042624-111827
  3. Int J Cancer. 2025 Aug 23.
    Single-cell multi-omics characterize colorectal tumors, adjacent healthy tissue and matched (tumor) organoids identifying CRC-unique features.
    Zhijun Yu, Merel Derksen, Brigit M Te Pas, Sabrina Ladstätter, Rene Overmeer, Peter Brazda, Marc van de Wetering, Farzin Pourfarzad, Robert G J Vries, Wout Megchelenbrink, Christoph Bock, Lucia Altucci, Hendrik G Stunnenberg.
      Colorectal cancer (CRC) arises in the colorectal tissue driven by genetic disorder or the accumulation of somatic mutations, leading to abnormal epithelial cell growth. In this study, we employed single-nucleus multi-omics analysis, including single-nucleus RNA-seq and single-nucleus ATAC-seq, on over 100,000 high-quality nuclei to investigate the molecular landscape of both primary tissue and patient-derived organoids (PDOs). Our analysis showed that normal PDOs (N-PDOs) derived from tissue adjacent to tumors replicate the cellular composition and differentiation trajectory of colorectal crypts. In contrast, tumor PDOs (T-PDOs) showed patient-specific transcriptomic and epigenomic heterogeneity yet consistently maintained a stem cell-like state. T-PDOs retained the somatic mutation profile of the primary tumor while also exhibiting de novo mutations not detected in either the primary tumor or N-PDOs. Notably, inferred cell-cell interaction analysis highlighted the activin signaling pathway as a potential unique feature of fibroblast-epithelial interactions within the tumor microenvironment. This study provides a comprehensive view of the transition from normal to malignant colorectal epithelium and underscores the utility of PDOs as a faithful model for capturing both conserved and patient-specific features of colorectal cancer.
    Keywords:  colorectal cancer (CRC); epigenomics; patient‐derived organoids (PDOs); single‐cell analysis; transcriptomics
    DOI:  https://doi.org/10.1002/ijc.70103
  4. Nat Cancer. 2025 Aug 25.
    Characterization of cis-regulatory elements and functional variants in colorectal cancer using epigenomics and CRISPRi screenings.
    Zequn Lu, Can Chen, Heng Zhang, Bin Li, Yizhuo Liu, Jiayi Guo, Runying Xu, Ke Shi, Qianying Ma, Ming Zhang, Yimin Cai, Jinyu Huang, Hui Geng, Linyun Fan, Caibo Ning, Yanmin Li, Shuoni Chen, Wen Tian, Kexin Hu, Haijie Li, Xiaojun Yang, Chaoqun Huang, Yongchang Wei, Xu Zhu, Xiangpan Li, Zhen Xiong, Ming Cai, Xiaoyang Wang, Shaokai Zhang, Hongda Chen, Min Dai, Kun Chen, Mingjuan Jin, Meng Jin, Ying Zhu, Jianbo Tian, Xiaoping Miao.
      Genetic variants associated with colorectal cancer (CRC) are primarily noncoding and reside in cis-regulatory elements (CREs), yet their underlying mechanisms remain elusive. Here we established a dynamic epigenetic atlas using multiomics data from 533 colorectal tissues spanning normal to advanced adenoma to cancer, identifying 7,492 differential CREs linked to 5,490 target genes. High-throughput CRISPR interference screening revealed 265 functional CREs involved in CRC cell proliferation. A polygenic risk score (PRS) based on functional CRE variants effectively predicted CRC and precancerous lesions among 476,770 individuals. Notably, the functional variant rs10871066 was significantly associated with increased risk of precancerous lesions and CRC (odds ratio = 1.27, P = 1.03 × 10-13). Mechanistically, rs10871066 triggers silencer-to-enhancer switching mediated by FOXP1 and TCF7L2, distally upregulating KLF5 to activate oncogenic pathways and PIBF1 to suppress natural killer cell cytotoxicity. Our study provides a comprehensive resource of dynamic epigenomic atlas, a functionally informed PRS for risk prediction and insights into epigenetic mechanisms underlying CRC development.
    DOI:  https://doi.org/10.1038/s43018-025-01031-z
  5. Sci Adv. 2025 Aug 22. 11(34): eadw3995
    Reverse control of biological networks to restore phenotype landscapes.
    Insoo Jung, Corbin Hopper, Seong-Hoon Jang, Hyunsoo Yeo, Kwang-Hyun Cho.
      Biological systems consist of genetic elements and their regulatory interactions, forming networks that maintain life. However, accumulated alterations such as DNA damage can distort biological behavior, leading to undesirable responses to stimulus. This raises the question of whether we can restore their nominal stimulus-response relationships. Current control approaches tend to enforce a single desired response rather than restore the proper capacity for variable responses to different stimulus. Here, we present an algebraic reverse control (ARC) framework for reversion of altered biological networks. ARC leverages matrix operations to quantify the phenotype landscape of the altered network and identifies reverse control targets for recovering the phenotype landscape of a nominal network. ARC is scalable to large Boolean networks and identifies effective control targets to restore biological behavior.
    DOI:  https://doi.org/10.1126/sciadv.adw3995
  6. Nat Rev Cancer. 2025 Aug 26.
    The evolution of cancer and ageing: a history of constraint.
    João Pedro de Magalhães.
      Ageing and cancer are ubiquitous in animals. They are fundamental and generally intrinsic to multicellular life. Nonetheless, ageing and cancer rates vary widely across species and understanding their evolution and interaction is of great biological interest. Although cancer arises from uncontrolled cell proliferation, ageing involves cell loss and degeneration, making them seemingly opposite yet interconnected processes. Because cancer can affect young individuals, natural selection will favour the evolution of cancer resistance over processes that maintain health in later life. As such, I propose that species evolve longer lifespans under the constraints imposed by the need to reduce cancer risk. Mechanisms that suppress cancer, such as telomere shortening and cellular senescence, may inadvertently promote ageing by limiting cell proliferation and tissue regeneration. Selection for tumour suppression may also impact stem cell ageing and contribute to the limited ability of adult tissues to regenerate. Overall, although cancer resistance is essential for the evolution of longevity, tumour suppression mechanisms may also contribute to ageing-related tissue degeneration and functional decline. Studying the trade-offs between the evolution of tumour suppression processes and their impact later in life may provide important insights into ageing processes.
    DOI:  https://doi.org/10.1038/s41568-025-00861-4
  7. Nature. 2025 Aug 27.
    Mechanical confinement governs phenotypic plasticity in melanoma.
    Miranda V Hunter, Eshita Joshi, Sydney Bowker, Emily Montal, Yilun Ma, Young Hun Kim, Zhifan Yang, Laura Tuffery, Zhuoning Li, Eric Rosiek, Alexander Browning, Reuben Moncada, Itai Yanai, Helen Byrne, Mara Monetti, Elisa de Stanchina, Pierre-Jacques Hamard, Richard P Koche, Richard M White.
      Phenotype switching is a form of cellular plasticity in which cancer cells reversibly move between two opposite extremes: proliferative versus invasive states1,2. Although it has long been hypothesized that such switching is triggered by external cues, the identity of these cues remains unclear. Here we demonstrate that mechanical confinement mediates phenotype switching through chromatin remodelling. Using a zebrafish model of melanoma coupled with human samples, we profiled tumour cells at the interface between the tumour and surrounding microenvironment. Morphological analysis of interface cells showed elliptical nuclei, suggestive of mechanical confinement by the adjacent tissue. Spatial and single-cell transcriptomics demonstrated that interface cells adopted a gene program of neuronal invasion, including the acquisition of an acetylated tubulin cage that protects the nucleus during migration. We identified the DNA-bending protein HMGB2 as a confinement-induced mediator of the neuronal state. HMGB2 is upregulated in confined cells, and quantitative modelling revealed that confinement prolongs the contact time between HMGB2 and chromatin, leading to changes in chromatin configuration that favour the neuronal phenotype. Genetic disruption of HMGB2 showed that it regulates the trade-off between proliferative and invasive states, in which confined HMGB2high tumour cells are less proliferative but more drug-resistant. Our results implicate the mechanical microenvironment as a mechanism that drives phenotype switching in melanoma.
    DOI:  https://doi.org/10.1038/s41586-025-09445-6
  8. Trends Genet. 2025 Aug 22. pii: S0168-9525(25)00196-9. [Epub ahead of print]
    Single-cell omics sequencing technologies: the long-read generation.
    Lu Wen, Fuchou Tang.
      Over the past decade, single-cell omics sequencing technologies have revolutionized biological and medical research and deepened our knowledge of cellular heterogeneities in life activities at the genomic, epigenomic, and transcriptomic levels. Concurrently, single-molecule long-read sequencing (SMS) technologies have also made amazingly rapid progress. In recent years, the convergence of these two exciting fields has injected new vitality into the generation of novel insights in genomics (repetitive elements, structural variations), epigenomics (allele-specific epigenetic modifications), and transcriptomics (alternative splicing) at the single-cell level, providing powerful new tools and opening new opportunities for biomedical fields. In this review, we introduce SMS platform-based single-cell genome, epigenome, and transcriptome sequencing technologies - the current situation and future perspectives.
    Keywords:  allele-specific epigenetic modification; alternative splicing; repetitive elements; single-cell omics sequencing; single-molecule long-read sequencing
    DOI:  https://doi.org/10.1016/j.tig.2025.07.012
  9. Nat Biotechnol. 2025 Aug 25.
    Systema: a framework for evaluating genetic perturbation response prediction beyond systematic variation.
    Ramon Viñas Torné, Maciej Wiatrak, Zoe Piran, Shuyang Fan, Liangze Jiang, Sarah A Teichmann, Mor Nitzan, Maria Brbić.
      Predicting transcriptional responses to genetic perturbations is challenging in functional genomics. While recent methods aim to infer effects of untested perturbations, their true predictive power remains unclear. Here, we show that current methods struggle to generalize beyond systematic variation, the consistent transcriptional differences between perturbed and control cells arising from selection biases or confounders. We quantify this variation in ten datasets, spanning three technologies and five cell lines, and show that common metrics are susceptible to these biases, leading to overestimated performance. To address this, we introduce Systema, an evaluation framework that emphasizes perturbation-specific effects and identifies predictions that correctly reconstruct the perturbation landscape. Using this framework, we uncover insights into the predictive capabilities of existing methods and show that predicting responses to unseen perturbations is substantially harder than standard metrics suggest. Our work highlights the importance of heterogeneous gene panels and disentangles predictive performance from systematic effects, enabling biologically meaningful developments in perturbation response modeling.
    DOI:  https://doi.org/10.1038/s41587-025-02777-8
  10. Nat Rev Genet. 2025 Aug 21.
    Imaging-based multimodal profiling of single cells with STAMP.
    Kellie Wise, Anna Pascual-Reguant.
      
    DOI:  https://doi.org/10.1038/s41576-025-00891-6
  11. EMBO Mol Med. 2025 Aug 26.
    Understanding cancer cell plasticity: EMT, respecialisation, and therapeutic opportunities.
    Anne-Pierre Morel, Maria Ouzounova.
      
    DOI:  https://doi.org/10.1038/s44321-025-00288-2
  12. Cancer Cell. 2025 Aug 13. pii: S1535-6108(25)00331-9. [Epub ahead of print]
    From gene lists to context drift.
    Zhongyang Lin, Dvir Aran.
      Treatment resistance limits long-term effectiveness in cancer therapy. Conventional biomarkers typically rely on static gene expression levels. In this issue of Cancer Cell, Jassim et al. report a new approach, RECODR, which captures how gene relationships shift over time, uncovering hidden drivers of resistance and suggesting effective combination treatments.
    DOI:  https://doi.org/10.1016/j.ccell.2025.07.025
  13. Commun Biol. 2025 Aug 22. 8(1): 1261
    3D collagen high-throughput screen identifies drugs that induce epithelial polarity and enhance chemotherapy response in colorectal cancer.
    Sarah J Harmych, Thomas P Hasaka, Chelsie K Sievers, Seung Woo Kang, Marisol A Ramirez, Vivian Truong Jones, Zhiguo Zhao, Oleg Kovtun, Claudia C Wahoski, Qi Liu, Ken S Lau, Robert J Coffey, Joshua A Bauer, Bhuminder Singh.
      Loss of polarity is a hallmark of cancer, and the related epithelial-to-mesenchymal transition (EMT) phenotype impacts prognosis and therapy outcomes, particularly in colorectal cancer (CRC). However, the mechanisms and drugs that impact EMT-related morphological changes are understudied, due to the complete failure of typical live/dead 2D high-throughput screens to capture morphology or the lack of robustness of 3D screens. We designed a high-throughput screen using 3D type I collagen cultures of CRC cells to assess morphological changes in colonies and identified several FDA-approved drugs that re-epithelialize CRC colonies. One of these drugs, azithromycin, increased colony circularity, enhanced E-cadherin membrane localization and ZO-1 localization to tight junctions, caused transcriptomic changes consistent with downregulation of EMT, and elevated sensitivity to the chemotherapeutic, irinotecan. A retrospective analysis of patient data demonstrated that the use of azithromycin in patients undergoing treatment for CRC with irinotecan had improved the 5 year survival compared to the chemotherapy alone. These results highlight the importance of morphological screens to identify novel drug candidates and synergistic mechanisms.
    DOI:  https://doi.org/10.1038/s42003-025-08699-0
  14. Sci Adv. 2025 Aug 22. 11(34): eadt1798
    Diverse oncogenes use common mechanisms to drive growth of major forms of human cancer.
    Otto Kauko, Mikko Turunen, Päivi Pihlajamaa, Antti Häkkinen, Rayner M L Queiroz, Mirva Pääkkönen, Sami Ventelä, Massimiliano Gaetani, Susanna L Lundström, Antonio Murgia, Biswajyoti Sahu, Johannes Routila, Gong-Hong Wei, Heikki Irjala, Julian L Griffin, Kathryn S Lilley, Teemu Kivioja, Sampsa Hautaniemi, Jussi Taipale.
      Mutations in numerous genes contribute to human cancer, with different oncogenic lesions prevalent in different cancer types. However, the malignant phenotype is simple, characterized by unrestricted cell growth, invasion, and often metastasis. One possible hypothesis explaining this dichotomy is that cancer genes regulate common targets, which then function as master regulators of essential cancer phenotypes. To identify mechanisms that drive the most fundamental feature shared by all tumors-unrestricted cell proliferation-we used a multiomic approach, which identified translation and ribosome biogenesis as common targets of major oncogenic pathways across cancer types. Proteomic analysis of tumors and functional studies of cell cultures established nucleolar and coiled-body phosphoprotein 1 as a key node, whose convergent regulation, both transcriptionally and posttranslationally, is critical for tumor cell proliferation. Our results indicate that lineage-specific oncogenic pathways regulate the same set of targets for growth control, revealing key downstream nodes that could be targeted for therapy or chemoprevention.
    DOI:  https://doi.org/10.1126/sciadv.adt1798
  15. Nat Rev Genet. 2025 Aug 20.
    Prospects for personalized cancer treatment in the era of single-cell sequencing.
    Daudi Jjingo.
      
    DOI:  https://doi.org/10.1038/s41576-025-00890-7
  16. World J Gastrointest Oncol. 2025 Aug 15. 17(8): 106663
    Challenges and proposed solutions to the adoption of cell free DNA in screening, detecting and prognosticating colorectal cancer.
    Megan Wern-Ee Chua, Dedrick Kok-Hong Chan.
      Detection and treatment of colorectal cancer (CRC) at an early stage is vital for long-term survival. Liquid biopsy has emerged as a promising new avenue for non-invasive screening of CRC as well as prognostication and surveillance of minimal residual disease. Cell free DNA (cfDNA) is a promising liquid biopsy analyte and has been approved for use in clinical practice. Here, we explore the current challenges of utilizing cfDNA in the screening and prognostication of CRC but also for detecting driver mutations in healthy, presymptomatic patients with normal colonic crypts. CfDNA for the detection of cancerous or premalignant colonic lesions has already been extensively explored, however few have considered utilizing cfDNA in the detection of driver mutations in healthy patients. Theoretically, this would allow us to detect patients who are at a higher risk of tumorigenesis decades in advance of established malignancy and stratify them into higher risk groups for early-intervention screening programs. We also explore the solutions necessary to overcome the challenges that prevent liquid biopsy from entering mainstream clinical use. The potential for liquid biopsy is immense if these challenges are successfully circumvented, and can dramatically reduce CRC rates as well as improve survival in patients.
    Keywords:  Cell free DNA; Circulating tumour deoxyribonucleic acid; Colorectal cancer; Detection; Liquid biopsy; Prognostication; Screening
    DOI:  https://doi.org/10.4251/wjgo.v17.i8.106663
  17. Cancer Lett. 2025 Aug 25. pii: S0304-3835(25)00573-7. [Epub ahead of print]633 218003
    Shifts in cancer funding: An overview of terminated research grants at the national cancer institute.
    Aakash Reddy, David T Zhu.
      
    DOI:  https://doi.org/10.1016/j.canlet.2025.218003
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