bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–04–05
eighteen papers selected by
Xiao Qin, University of Oxford
  1. Gene regulatory landscape dissected by single-cell four-omics sequencing.
  2. Therapeutic manipulation and spatial quantification of the tumor microenvironment in colorectal cancer.
  3. Single-cell and spatial profiling in cancer biology and clinical oncology.
  4. Redefining cancer drivers with tissue-specific context.
  5. Constructing a holistic map of cell fate decision by hyper solution landscape.
  6. Pathophysiology of colitis-associated colorectal cancer.
  7. Advancing Cancer Prevention through Precision Prediction.
  8. A toolkit for modeling cis-regulatory logic of enhancers at large scale.
  9. Early-Life Mutagenesis and the Rise of Early-Onset Colorectal Cancer.
  10. In vitro models of cell competition: current approaches and future directions.
  11. Integrated Single‑Cell and Spatial Transcriptomics Reveal the Colorectal Cancer Microenvironment.
  12. Reconstructing tumor tissues in 3D: From organoids to bioengineered niches.
  13. A snapshot of the earliest stages of hepatocellular carcinoma.
  14. Spatial omics insights into tumor myeloid cells: roles in tumorigenesis, prognosis, and therapy.
  15. Announcing the Lancet Commission on colorectal cancer: addressing the rising global burden.
  16. Patient-derived intestinal organoids as a model for site-specific mucosal bacterial interactions in paediatric inflammatory bowel disease.
  17. Unexpected role of the integrated stress response in cancer immune evasion.
  18. Pre-existing cell states predict resistance to multiple treatments.
  1. Nature. 2026 Apr 01.
    Gene regulatory landscape dissected by single-cell four-omics sequencing.
    Yujie Chen, Zhiyuan Liu, Heming Xu, Jiayu Liu, Mengxuan Wang, Yi Chi, Boyuan Liang, Menghan Liu, Yongli Peng, Hao Ge, Dong Xing.
      Cellular diversity is governed not only by the transcriptome but also by multiple layers of epigenomic regulation, including nucleosome occupancy, chromatin states and genome architecture1-3. Here, to comprehensively understand how these regulatory modalities converge to shape cellular identity, we developed a single-cell four-omics sequencing method that enables parallel profiling of genome conformation, histone modifications, chromatin accessibility and gene expression within the same cell (CHARM). Applying CHARM to mouse embryonic stem cells and cortical tissues, we reconstructed integrated epigenome profiles, uncovering distinct cell-cycle dynamics of chromatin accessibility and histone modification, and spatial clustering of regulatory elements in three-dimensional nuclear space. Leveraging an interpretable machine learning model, we further identified thousands of enhancer-promoter linkages with high accuracy that modulate gene expression in a cell-type- and subtype-specific manner. Together, CHARM enables integrative dissection of the three-dimensional epigenome at single-cell resolution, providing a versatile platform for decoding the regulatory landscape across diverse cells in complex tissues.
    DOI:  https://doi.org/10.1038/s41586-026-10322-z
  2. iScience. 2026 Apr 17. 29(4): 115193
    Therapeutic manipulation and spatial quantification of the tumor microenvironment in colorectal cancer.
    Eoghan J Mulholland-Illingworth, Joshua W Moore, Muyang Lin, Raheleh Amirkhah, Lucile Grzesiak, Amelia Ligeza, Joshua A Bull, Joseph Boen, Gabriel N Valbuena, Michael A Gillespie, Tamsin R M Lannagan, Kathryn Gilroy, Megan L Mills, Shania M Corry, Rachel A Ridgway, Hayley L Belnoue-Davis, Philip D Dunne, Owen J Sansom, Helen M Byrne, Simon J Leedham.
      Colorectal cancer (CRC) is a complex ecosystem shaped by bidirectional interactions between epithelium and the tumor microenvironment, prominently mediated by TGFβ signaling. Cancer-associated fibroblasts (CAFs) are regulators of epithelial plasticity and immune cell recruitment; yet, their diversity has impacted translationally applicable spatial analysis. Here, we distil the fibroblast continuum into two overarching CAF populations that are largely transcriptomically distinct and are marked by PDGFRA+ and ACTA2+ expression, enabling robust spatial identification using single immunohistochemical markers. We show that TGFβ signaling drives dynamic transitions between these states. In a preclinical model, selective ALK5 inhibition remodels CAF composition in vivo, reconfiguring local immune neighborhoods and indirectly altering epithelial stem cell states. Finally, we demonstrate that multiscale spatial analysis provides a quantitative readout of stromal-immune-epithelial remodeling following therapy. These findings establish a simplified, translationally relevant CAF framework and highlight spatially resolved stromal dynamics as measurable indicators of therapeutic response in CRC.
    Keywords:  cancer; health sciences; medicine; oncology
    DOI:  https://doi.org/10.1016/j.isci.2026.115193
  3. Nat Cancer. 2026 Apr 03.
    Single-cell and spatial profiling in cancer biology and clinical oncology.
    Chris J Frangieh, Joy Linyue Fan, Johannes C Melms, Parin Shah, Elham Azizi, Benjamin Izar.
      Multiple single-cell and spatial genomics tools have transformed our ability to deconvolve intricate diseases, including cancer. Analysis of complex, multimodal data has provided insights into genomics, cellular states and interactions in tumor ecosystems, enabling the dissection of salient biology and expanding our understanding of drug response, resistance and target discovery. However, several challenges remain before these methods can achieve their full clinical potential. Here, we discuss opportunities, barriers and potential solutions, including sample acquisition and preservation approaches, profiling methods and analytical tools for heterogeneous populations, and we provide recommendations for robust, reproducible use of these technologies in clinical settings.
    DOI:  https://doi.org/10.1038/s43018-026-01142-1
  4. Cancer Cell. 2026 Apr 02. pii: S1535-6108(26)00161-3. [Epub ahead of print]
    Redefining cancer drivers with tissue-specific context.
    Maria Kalyva, Nicholas McGranahan.
      In this issue of Cancer Cell, Bandlamudi and colleagues analyze over 50,000 tumors spanning 64 cancer types, revealing how tissue context dictates the prevalence and evolutionary timing of somatic driver alterations. Their findings underscore the need to move away from a purely gene-centric view of oncology toward a context-aware framework.
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.007
  5. Cell Syst. 2026 Mar 27. pii: S2405-4712(26)00044-X. [Epub ahead of print] 101562
    Constructing a holistic map of cell fate decision by hyper solution landscape.
    Xiaoyi Zhang, Zhiyuan Li, Lei Zhang.
      The Waddington landscape metaphor has inspired extensive quantitative studies of cell fate decisions using dynamical systems. While these approaches provide valuable insights, the intrinsic nonlinear complexity and the parameter dependence limit systematic analysis of fate transitions. Here, we introduce the hyper solution landscape (HSL), a minimally parameter-dependent methodology showing a comprehensive structure of all possible landscape configurations for gene regulatory networks. HSL connects different solution landscapes to reflect dynamic changes in the landscapes associated with bifurcations. Applied to the cross-inhibition with self-activation motif, HSL analysis identifies key hyperparameters driving distinct directional changes in cell-fate propensity. Different routes through the HSL between the same initial and final states can produce markedly different fate distributions. This enables the rational design of transition strategies. We validate the HSL's utility in the seesaw model of cellular reprogramming, establishing a powerful framework for understanding and engineering cell-fate decisions. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  Waddington landscape; bifurcation; cell fate decision; gene regulatory network; hyper solution landscape; solution landscape
    DOI:  https://doi.org/10.1016/j.cels.2026.101562
  6. Nat Rev Gastroenterol Hepatol. 2026 Apr 01.
    Pathophysiology of colitis-associated colorectal cancer.
    Clemens Neufert, Markus F Neurath.
      Colitis-associated colorectal cancer (caCRC) is a subset of lower gastrointestinal tract malignancies that occurs in patients with inflammatory bowel disease (IBD), such as ulcerative colitis and Crohn's disease. The global prevalence of IBD is increasing, putting more individuals at risk of developing caCRC. The pathophysiological mechanisms that underlie the initiation and growth of caCRC remain to be fully elucidated. Nevertheless, studies have provided novel insights into the pathophysiology of caCRC, underscoring the distinguishing characteristics of caCRC compared with sporadic forms of CRC. In this Review, we describe the key mechanisms that drive caCRC. Starting from a clinical perspective and highlighting key features of the tumour epithelium, we discuss typical caCRC-related characteristics among subtypes of CRC, with a particular focus on the role of stromal cells in the tumour microenvironment. In addition, we review the contributions of immune cells to tumour control versus tumour promotion, and how signals from the gut microbiome might influence tumour development in caCRC. We also discuss various aspects of the pathophysiological heterogeneity of caCRC. Finally, we outline potential implications for therapy, and how these findings could be translated into future strategies of personalized medicine targeting caCRC.
    DOI:  https://doi.org/10.1038/s41575-026-01197-6
  7. Cancer Discov. 2026 Apr 01. 16(4): 647-650
    Advancing Cancer Prevention through Precision Prediction.
    Miquel Angel Pujana, Joan Brunet, Antonis C Antoniou.
      Emerging knowledge, integrative frameworks, and multidisciplinary partnerships together create an unprecedented opportunity to advance cancer prevention through precision. By combining multimodal risk assessment with causal biological insight and dynamic models of early carcinogenesis, precision prevention can enable actionable, equitable, and acceptable preventive and interception strategies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2235
  8. Nat Methods. 2026 Apr 04.
    A toolkit for modeling cis-regulatory logic of enhancers at large scale.
      
    DOI:  https://doi.org/10.1038/s41592-026-03058-1
  9. Cancer Discov. 2026 Apr 01. 16(4): 644-646
    Early-Life Mutagenesis and the Rise of Early-Onset Colorectal Cancer.
    Ludmil B Alexandrov, Paul Brennan, Michael R Stratton.
      Colorectal cancer incidence is rising globally among individuals younger than 50 years and remains poorly explained by established risk factors. In this study, we advance the hypothesis that early-childhood exposure to mutagen-producing bacteria contributes to lifetime colorectal cancer risk by imprinting oncogenic mutations in the developing colorectal epithelium, thereby initiating tumorigenesis decades before clinical diagnosis and redefining early-onset colorectal cancer as a disease rooted in early-life mutagenic exposure.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0166
  10. Oncogene. 2026 Mar 28.
    In vitro models of cell competition: current approaches and future directions.
    Selami Baglamis, Przemek M Krawczyk, Louis Vermeulen, Sanne M van Neerven, Kristiaan J Lenos.
      Cell competition is an evolutionarily conserved quality control mechanism that eliminates less-fit cells to ensure optimal tissue integrity during development, homeostasis, and regeneration. Beyond these physiological roles, recent evidence implicates a role for cell competition in disease, particularly in cancer, where it can function by either suppressing or promoting malignant progression. In this review, we provide an overview of the different molecular mechanisms that drive cell competition and their impact on cancer development and progression. We will evaluate the current state-of-the-art in vitro experimental systems that can be employed to study these processes. Ranging from classical 2D co-culture systems to advanced organoid and organ-on-chip platforms, these model systems collectively enhance our understanding of the complex cellular interactions that underlie the competitive differences between cells. By integrating insights from diverse model systems, we highlight how cell competition shapes tumor dynamics and discuss how this knowledge could inspire novel therapeutic strategies to prevent or control tumor growth.
    DOI:  https://doi.org/10.1038/s41388-026-03751-7
  11. Crit Rev Oncol Hematol. 2026 Mar 31. pii: S1040-8428(26)00198-8. [Epub ahead of print] 105311
    Integrated Single‑Cell and Spatial Transcriptomics Reveal the Colorectal Cancer Microenvironment.
    Ruihan Yang, Shijia Hu, Kaifan Li, Haoyi Wang, Xiang Zhou, Tao Han, Liping Guan.
      Colorectal cancer (CRC) is a malignancy with high global incidence and mortality rates, necessitating innovative approaches to decipher its biological characteristics and clinical behaviors. The integration of single-cell sequencing and spatial transcriptomics has emerged as a revolutionary tool in CRC research. Single-cell sequencing uncovers tumor heterogeneity and interaction networks, while spatial transcriptomics precisely maps the cellular distribution and tissue architecture within the tumor microenvironment (TME). This integrated approach has revealed spatially organized tumor-stroma-immune networks-including immune-excluded zones characterized by CAF-mediated ECM barriers and SPP1⁺ TAMs, immune-active niches featuring T cell-myeloid cooperation, and TLS-associated domains with both activating and suppressive microenvironments. Key discoveries include MGP-high epithelial cells driving liver metastasis via NF-κB-mediated PD-L1 upregulation, SPP1⁺ CAFs forming immunosuppressive metastatic niches, and functionally validated mechanisms such as IL1R1⁺ iCAFs inducing M2 polarization and MDK-SDC4 interactions promoting Treg migration. These findings identify candidate biomarkers (e.g., TIMP1, SPP1⁺ CAFs) and potential therapeutic targets (e.g., IL1R1⁺ iCAFs, MDK-SDC4 axis) with clinical relevance. This review summarizes recent advances in the application of these integrated technologies for CRC research, discusses their prospects and challenges in characterizing tumors and advancing precision diagnostics and therapeutics, and presents a theoretical framework to guide future research and clinical practice in the study and treatment of CRC.
    Keywords:  Colorectal cancer; Immunotherapy; Single-cell sequencing; Spatial transcriptomics; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105311
  12. Cell Stem Cell. 2026 Apr 02. pii: S1934-5909(26)00115-3. [Epub ahead of print]33(4): 546-570
    Reconstructing tumor tissues in 3D: From organoids to bioengineered niches.
    Verena J Kast, Fatemeh Navaee, Majid Halvaei, Stefan Liebau, Ninel Azoitei, Markus Breunig, Peter Loskill, Alexander Kleger.
      Tumor tissue engineering, integrating organoid, microfluidic, and biofabrication technologies, has opened new avenues for cancer research. Leveraging advanced bioengineering and biomaterials, these 3D models capture tumor architecture, cellular heterogeneity, biomechanics, and biochemical characteristics for disease modeling. Despite recognition that tissue organization influences malignancy and drug resistance, clinically oriented 3D approaches are rare, largely due to tumor microenvironment complexity, cellular plasticity, and interpatient heterogeneity. With a primary emphasis on gastrointestinal malignancies, we outline the capabilities and remaining limitations of organoid-based cancer models, including developmentally defined stem cell-derived systems that enable controlled early-stage modeling when premalignant material is scarce. We discuss patient-derived organoids as clinical avatars for therapy response prediction and summarize recent clinical trials that delineate key bottlenecks hindering routine implementation. Finally, we outline how innovations in biomaterial design, biofabrication, and microfluidics, benchmarking against patient data, and artificial intelligence are converging to better reconstruct tumor complexity, improve experimental tractability, and accelerate translation.
    Keywords:  AI; biofabrication; biomaterials; cancer; clinical translation; microfluidics; organoids
    DOI:  https://doi.org/10.1016/j.stem.2026.03.005
  13. Cancer Cell. 2026 Apr 02. pii: S1535-6108(26)00162-5. [Epub ahead of print]
    A snapshot of the earliest stages of hepatocellular carcinoma.
    Álvaro Andrades, Jan O Korbel.
      How premalignant tissue transforms into cancer remains an open question. In this issue of Cancer Cell, Zhang et al. address this by comparing early hepatocellular carcinomas with matched premalignant tissue, revealing potential paths for malignant transformation: one characterized by high copy-number alteration burden and one characterized by high inflammation.
    DOI:  https://doi.org/10.1016/j.ccell.2026.03.008
  14. Mol Biol Rep. 2026 Mar 31. pii: 568. [Epub ahead of print]53(1):
    Spatial omics insights into tumor myeloid cells: roles in tumorigenesis, prognosis, and therapy.
    Bugi Ratno Budiarto, Pimpin Utama Pohan.
      Tumor-associated myeloid cells form a highly plastic and spatially organized immune compartment that plays a central role in tumor evolution, clinical outcome, and therapeutic response. Single-cell RNA sequencing has revealed extensive heterogeneity among macrophages, monocytes, neutrophils, dendritic cells, and related lineages, uncovering transcriptional programs linked to tumor promotion or immune activation. However, the dissociative nature of single-cell approaches disrupts tissue architecture, limiting insight into how myeloid cells interact with malignant, stromal, and lymphoid populations within intact tumors. Recent advances in spatial omics technologies address this limitation by preserving tissue context while enabling high-dimensional profiling of RNA and protein expression in situ. In this review, we synthesize emerging spatial proteomic and transcriptomic studies of tumor-associated myeloid cells, identify recurrent spatial architectures that govern tumorigenesis, prognosis, and treatment response, and examine analytical frameworks that translate spatial patterns into mechanistic understanding. By moving beyond descriptive spatial maps, we highlight unifying biological principles and translational opportunities that position myeloid spatial organization as a critical determinant of cancer progression and precision oncology.
    Keywords:  Clinical implication; Spatial-omics; Tumor-associated myeloid cells; Tumorigenesis
    DOI:  https://doi.org/10.1007/s11033-026-11758-2
  15. Lancet. 2026 Mar 26. pii: S0140-6736(26)00418-6. [Epub ahead of print]
    Announcing the Lancet Commission on colorectal cancer: addressing the rising global burden.
    Lancet Commission on Colorectal Cancer
      
    DOI:  https://doi.org/10.1016/S0140-6736(26)00418-6
  16. Sci Rep. 2026 Apr 01.
    Patient-derived intestinal organoids as a model for site-specific mucosal bacterial interactions in paediatric inflammatory bowel disease.
    Eva Chan, Wing Hei Chan, Genevieve Kerr, Stuart K Archer, Thierry Jardé, Rebekah M Engel, Jodee A Gould, Shanika L Amarasinghe, Emily L Rutten, Gemma L D'Adamo, Emily L Gulliver, Linden J Gearing, Samuel C Forster, Edward M Giles, Helen E Abud.
      Inflammatory bowel disease (IBD) is secondary to an abnormal immune response to the microbiota. To study this, models of host-microbe interactions that represent mucosal bacterial communities and inter-patient diversity are required. Human intestinal organoids (HIOs) are an established model to investigate epithelial responses. Here, we describe a technique of culturing bacteria directly from the sites of inflammation in IBD, while simultaneously sampling host tissue. We generated HIOs from a cohort of newly diagnosed paediatric IBD patients, without confounding treatments or comorbidities, and explored their response to site-specific bacteria. A unique biobank of matched HIOs and cultured mucosa-attached bacteria was established from 27 paediatric patients. Transcriptional profiling revealed differential gene expression between control and IBD-derived organoids. We used microinjection to introduce bacteria to the apical surface of the epithelium, to determine the effect of bacteria on host epithelial cells. We measured survival and growth of bacteria within the HIOs and tested several related bacterial isolates for their impact on the epithelium. An isolate from a control patient stimulated inflammatory signalling pathways but this was not observed in response to a closely related isolate originating from an IBD patient. This study demonstrates the feasibility of isolating bacteria and generating organoids from the same biopsy tissue, to explore personalised host-microbe interactions. The microinjections, while labour-intensive, demonstrate that closely related bacteria can induce very different epithelial responses, with downstream implications for immune response. This highlights the importance of understanding host-microbe interactions in a strain- and site-specific manner and developing techniques for personalised microbiome-based therapeutics.
    Keywords:  Bacteria-organoid co-culture; Microinjection; Paediatric inflammatory bowel disease; Patient-derived organoids
    DOI:  https://doi.org/10.1038/s41598-026-46184-8
  17. Trends Cancer. 2026 Apr 01. pii: S2405-8033(26)00056-7. [Epub ahead of print]
    Unexpected role of the integrated stress response in cancer immune evasion.
    Lucia Borriello, Lorenzo Galluzzi.
      Viral mimicry, i.e., the ability of uninfected cancer cells to emit molecular signals normally associated with infection, is paramount for anticancer immunity. Recent findings from Bossowski et al. indicate that the integrated stress response (a crucial component of cellular responses against infection) can unexpectedly promote immune evasion via an LCN2-driven, macrophage-dependent mechanism.
    Keywords:  ATF4; ER stress response; SLC22A17; T cell exclusion; immunogenic cell death; three Cs
    DOI:  https://doi.org/10.1016/j.trecan.2026.03.001
  18. Cell Genom. 2026 Mar 30. pii: S2666-979X(26)00053-4. [Epub ahead of print] 101191
    Pre-existing cell states predict resistance to multiple treatments.
    Dylan L Schaff, Phoebe E White, Christopher J Cote, Grace E Watterson, Kevin Z Lin, Aria J Fasse, Nancy R Zhang, Sydney M Shaffer.
      Pre-existing differences between individual cancer cells can predict which cells will become resistant to treatment. DNA barcoding methods that track clones and their cell states during treatment have furthered this understanding, previously focusing on resistance to single treatments. Here, we performed multi-treatment, high-throughput clonal tracking and single-cell RNA sequencing to trace rare clones through resistance development across many treatments in parallel, identifying cell states associated with multi-treatment resistance. We found that clones resistant to one treatment had an increased chance of separately developing resistance to other treatments. We identified high CD44 expression in treatment-naive cells as a predictor of future multi-treatment resistance. Additionally, we found that differences in pre-treatment gene expression states can lead cells within the same treatment condition to follow divergent paths toward their ultimate resistance fate. This work provides a framework for extracting targetable gene expression states from complex resistance dynamics to eliminate multi-treatment resistance.
    Keywords:  clonal tracing; melanoma; scRNA-seq; treatment resistance
    DOI:  https://doi.org/10.1016/j.xgen.2026.101191
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