bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–03–08
seventeen papers selected by
Xiao Qin, University of Oxford
  1. Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a Fetal-Like State in the Intestinal Epithelium.
  2. A tumultuous journey that led to AI in cancer.
  3. Precancerous niche remodelling dictates nascent tumour persistence.
  4. Stress-hormone signalling protects spreading cancer cells from immune system.
  5. Cell-free chromatin state tracing reveals disease origin and therapy responses.
  6. Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy.
  7. Canonical BAF chromatin remodeling complex specifies stem cell fate via cell-type-specific co-factor recruitment.
  8. Claudin proteins as emerging therapeutic targets for solid tumours.
  9. Macrophage heterogeneity and plasticity: mechanism and therapeutics.
  10. Metabotherapy for intestinal disease: using metabolites to prevent and treat disorders of the gut.
  11. The Increase of Early-Onset Colorectal Cancer: New Insights and Emerging Hypotheses.
  12. Genetically encoded assembly recorder temporally resolves cellular history.
  13. A different perspective on the cancer stem cell theory.
  14. DECODE: deep learning-based common deconvolution framework for various omics data.
  15. Spatial transcriptomics maps host-gut microbiome biogeography at high resolution.
  16. Bringing AI to Cancer's Regulatory Genome.
  17. Harnessing genomics for early cancer detection, risk stratification and prevention.
  1. Cancer Res. 2026 Mar 05.
    Dynamic Reprogramming of PDGFRA-Expressing Stromal Cells Facilitates WNT-Driven Transformation by Promoting a Fetal-Like State in the Intestinal Epithelium.
    Oscar Pellon-Cardenas, Prateeksha Rout, Sohaib Hassan, Emily Fokas, Isha Patel, Jay Patel, Xia Qiu, Ping He, Olivia Nussbaum, Alex Wu, Rohit Kumar, Masuda Akther, Alexandra Logerfo, Siwen Wu, Daniel Wagner, Dario Boffelli, Katherine D Walton, Kevin Tong, Jahangir Iqbal, Ruoxuan Xiao, Lei Chen, Jason R Spence, Nicholas J Bessman, Elisa Manieri, Ramesh A Shivdasani, Michael P Verzi.
      Stromal fibroblasts of the mesenchyme regulate critical signaling gradients along the crypt-villus axis in the intestine and provide a niche that supports intestinal stem cells. Here, we reported that PDGFRA-expressing fibroblasts secrete ligands that promote a fetal-like state in the intestinal mucosa during early WNT-mediated tumorigenesis. Data from a mouse model of WNT-driven oncogenesis and single-cell RNA sequencing (RNA-seq) of mesenchyme cell populations revealed a dynamic reprogramming of PDGFRA+ fibroblasts that facilitates WNT-mediated tissue transformation. Functional assays of potential mediators of cell-to-cell communication between these fibroblasts and the oncogenic epithelium revealed that TGFβ signaling is notably induced in PDGFRA+ fibroblasts in the presence of oncogenic epithelium, and TGFβ was essential to sustain fetal-like growth of organoids ex vivo. Reduction of CDX2 in β-catenin mutant intestinal epithelium elevated the fetal-like transcriptome and accelerated WNT-dependent oncogenic transformation in vivo. These results demonstrate that PDGFRA+ fibroblasts are activated during WNT-driven oncogenesis to promote a fetal-like state in the epithelium that precedes and facilitates tumor formation.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0101
  2. Nat Cancer. 2026 Mar 04.
    A tumultuous journey that led to AI in cancer.
    Eytan Ruppin.
      
    DOI:  https://doi.org/10.1038/s43018-026-01134-1
  3. Nature. 2026 Mar 04.
    Precancerous niche remodelling dictates nascent tumour persistence.
    G Skrupskelyte, J E Rojo Arias, H Ajith, Y Dang, D Rossetti, S Han, M K S Tang, M T Bejar, B Colom, J C Fowler, K Murai, W Knight, D Aust, M H H Schmidt, J Jászai, S Zeki, A Noorani, P H Jones, S Rulands, B D Simons, M P Alcolea.
      Interactions between mutant cells and their environment have a key role in determining cancer susceptibility1-3. However, understanding of how the precancerous microenvironment contributes to early tumorigenesis remains limited. Here we show that newly emerging tumours at their most incipient stages shape their microenvironment in a critical process that determines their survival. Analysis of nascent squamous tumours in the upper gastrointestinal tract of the mouse reveals that the stress response of early tumour cells instructs the underlying mesenchyme to form a supportive 'precancerous niche', which dictates the long-term outcome of epithelial lesions. Stimulated fibroblasts beneath emerging tumours activate a wound-healing response that triggers a marked remodelling of the underlying extracellular matrix, resulting in the formation of a fibronectin-rich stromal scaffold that promotes tumour growth. Functional heterotypic 3D culture assays and in vivo grafting experiments, combining carcinogen-free healthy epithelium and tumour-derived stroma, demonstrate that the precancerous niche alone is sufficient to confer tumour properties to normal epithelial cells. We propose a model in which both mutations and the stromal response to genetic stress together define the likelihood of early tumours to persist and progress towards more advanced disease stages.
    DOI:  https://doi.org/10.1038/s41586-026-10157-8
  4. Nature. 2026 Mar 04.
    Stress-hormone signalling protects spreading cancer cells from immune system.
      
    Keywords:  Cancer; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-00650-5
  5. Nature. 2026 Mar 04.
    Cell-free chromatin state tracing reveals disease origin and therapy responses.
    Xubin Chen, Xiaoxuan Meng, Weilong Zhang, Xiawei Zhang, Yaping Zhang, Ping Yang, Yan Liu, Fang Bao, Sen Li, Jing Wang, Changjian Yan, Chunyuan Li, Lingke Zhang, Xiaoyu Hao, Jia Liu, Jing Sun, Zhengting Wang, Yu Tian, Liqing Zhu, Yan Hou, Zongchao Liu, Wenqing Li, Lan Mi, Xinyu Qi, Yanzhu Yue, Peng Du, Guoqiang Chen, Junke Zheng, Liping Dou, Hongmei Jing, Aibin He.
      Cell-free DNA in blood originates from fragmented chromatin released by dying cells from both healthy and diseased tissues1,2. These fragments carry rich molecular modalities that can reveal pathological alterations in tissues of origin3-10. Here we develop cf-EpiTracing, a highly sensitive automated platform that profiles histone modifications in cell-free DNA from as little as 50 μl of human plasma. By integrating multimodal chromatin states with machine learning, cf-EpiTracing enables accurate deconvolution of cell types of origin. We generated 2,417 cf-EpiTracing profiles from plasma of 125 healthy individuals and 549 patients with inflammatory bowel disease, colorectal cancer, coronary heart disease or lymphoma. cf-EpiTracing enabled unbiased identification of primary diseased tissues and other organ involvement, stratification of B cell lymphoma subtypes with different genetic and epigenetic underpinnings, and detection of early-stage diseases or lesions. Surveying dynamics of epigenetic signatures uncovered disease transformation from follicular lymphoma to diffuse large B cell lymphoma. Further, cf-EpiTracing revealed genomic translocations and epigenetic alterations in patients with mantle cell lymphoma. Of note, our study leverages holistic epigenetic signatures, independently of knowledge of gene transcription, to accurately report recurrence risk and therapeutic response. Together, these findings establish cf-EpiTracing as an automated, non-invasive, epigenome-centric framework with broad applications in early diagnosis, molecular subtyping and prognostic prediction.
    DOI:  https://doi.org/10.1038/s41586-026-10224-0
  6. Nat Commun. 2026 Mar 06.
    Necroptosis in both tumour and stromal compartments determines responsiveness to immunogenic cell death-based immunotherapy.
    Winnie Fernando, Jarama Clucas, Alberto Rizzo, Ramsay Singer, Emily Goode, Crescens Tiu, Scott Layzell, Joshua Konecnik, Rebecca Wilson, Sidonie Wicky John, Samuel Jouny, Naomi Guppy, Victoire Boulat, Jonathan Mannion, Maria Goicoechea, Shaun Tan, Sam Lawson, Chris Starling, Gabrielle Elshtein, Nivedita Ravindran, Anna B Montgomery, Rosa Andres-Ejarque, Mark Allen, Steven Lumbard, Fredrik Wallberg, Kai Betteridge, Ross Scrimgeour, David Robertson, George Ward, Martin Sims, Tomoko Smyth, Andre L Samson, James M Murphy, Daniela Kolarevic Ivankovic, Esther N Arwert, Dinis P Calado, Anita Grigoriadis, Matthew J Smalley, Alan Melcher, Syed Haider, Toby Lawrence, Ioannis Roxanis, Andrew N J Tutt, Tencho Tenev, Pascal Meier.
      Immunotherapy has transformed cancer treatment, including early triple-negative breast cancer (TNBC), yet most patients with advanced TNBC fail to respond to immune checkpoint blockade (ICB) plus chemotherapy. Durable control likely requires not only tumour cell killing but also immunogenic cell death (ICD) that activates antitumour immunity. Using a Brca1⁻/⁻p53⁻/⁻ organoid-derived TNBC model that recapitulates the immune landscapes of basal-like tumours, we show that RIPK1-driven ICD synergises with anti-PD-1 therapy to induce durable tumour control and immune memory in immune-infiltrated tumours. Mechanistically, both tumour-intrinsic and stromal necroptosis are required. Deletion of Ripk1 or Mlkl in tumour cells, or Mlkl in the stromal compartment, markedly impairs therapeutic efficacy. Moreover, immunologically "cold" tumours can be rendered responsive to ICD-based therapy by STING agonists. These findings demonstrate that the benefit of IAP antagonism with checkpoint blockade critically depends on coordinated necroptosis in both tumour and stromal cells, underscoring the need to integrate tumour microenvironmental context when designing ICD-targeted immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-026-70133-8
  7. Nat Commun. 2026 Mar 03.
    Canonical BAF chromatin remodeling complex specifies stem cell fate via cell-type-specific co-factor recruitment.
    Mingyi Zhang, Jifan Feng, Tingwei Guo, Lin Meng, Fei Pei, Lu Gao, Yuchen Yang, Thach-Vu Ho, Yang Chai.
      Individual subunits within the canonical BAF (cBAF) chromatin remodeling complex are known to regulate stem cell behavior, with some functional redundancy across subunits. Yet, how the cBAF complex directs adult stem cell fate specification and maintains stem cell niches remains unclear. Using the adult mouse incisor, we show that cBAF specifies mesenchymal stem cell (MSC) fate by recruiting distinct transcriptional co-factors to shape cell-type-specific chromatin regulation. Through single-cell multi-omics and in vivo functional analyses, we identify ARID1-containing cBAF as an essential gatekeeper that maintains the dynamic balance between MSC self-renewal and differentiation. Specifically, cBAF-DLX2 interactions preserve niche identity by remodeling intronic chromatin accessibility of niche-defining marker Runx2, while cBAF-FOXO1 directly modulates promoter accessibility of lineage-regulating transcription factors, including STAT3 and TRP53, among others, to balance progenitor proliferation and differentiation. Functional perturbation of RUNX2 and TRP53 confirms their roles downstream of cBAF in niche maintenance and fate specification. Our findings establish cBAF as a central regulator of adult stem cell niches and lineage commitment, and highlight cofactor-dependent mechanisms that may have broader implications for tissue regeneration and BAF-associated disorders.
    DOI:  https://doi.org/10.1038/s41467-026-70038-6
  8. Nat Rev Cancer. 2026 Mar 02.
    Claudin proteins as emerging therapeutic targets for solid tumours.
    Antonio Saviano, Alberto Toso, Samuel J Klempner, Thomas F Baumert.
      Claudins (CLDNs) are transmembrane proteins that contribute to the epithelial cell polarity and integrity of tight junctions in healthy tissues. CLDNs are frequently overexpressed across different solid tumours, and expression correlates with tumour subtype, grade and prognosis. Dysregulated CLDN expression modulates oncogenic signalling and contributes to tumour proliferation, epithelial-mesenchymal transition, stemness, fibrosis, immune modulation and therapeutic resistance. Owing to their frequent overexpression and functional role in cancer biology, CLDNs have emerged as attractive therapeutic targets. Their surface expression can be exploited to guide therapies into tumours. For example, a monoclonal antibody targeting the CLDN18.2 isoform has reached clinical approval, validating the potential of CLDN-directed approaches. Additional strategies such as antibody-drug conjugates, bispecific and trispecific antibodies and chimeric antigen receptor (CAR) T cells are in development for several CLDN family members. Targeting intracellular CLDN domains or their downstream signalling to disrupt their biological function may offer further promise. Here, we review the functional role of CLDN biology in solid tumours, summarize the clinical development of therapeutic approaches and discuss opportunities for biomarker-enriched patient selection. Collectively, we highlight CLDN targeting as a precision oncology approach relevant to multiple solid tumours.
    DOI:  https://doi.org/10.1038/s41568-026-00913-3
  9. Trends Pharmacol Sci. 2026 Mar 05. pii: S0165-6147(26)00031-3. [Epub ahead of print]
    Macrophage heterogeneity and plasticity: mechanism and therapeutics.
    Shiming Li, Yurui Yang, Haibo Qiu, Lizhi Pang.
      Macrophages play pivotal roles in regulating immune responses during inflammation and cancer. Recent evidence indicates that macrophages are dynamic cells capable of switching between different functional states in response to stimuli from their local microenvironment. However, characterizing these functional states in the context of inflammation and cancer has been challenging due to a lack of powerful tools. To address this important issue, recent studies have employed single-cell technologies and emerging immunoinformatics methods to explore the relationship between macrophage phenotypic states and their cellular functions. Here, we synthesize insights from these studies and discuss the current understanding of macrophage diversity (heterogeneity) and adaptability (plasticity) in acute inflammation, chronic diseases, and cancer. We also highlight the molecular mechanisms that initiate macrophage state transitions during disease progression. By integrating knowledge gained from different disease models, we propose a conceptual framework for the future development of pharmacological approaches aimed at targeting macrophages effectively.
    Keywords:  cancer; heterogeneity; inflammation; macrophage; plasticity
    DOI:  https://doi.org/10.1016/j.tips.2026.02.002
  10. Nat Rev Gastroenterol Hepatol. 2026 Mar 02.
    Metabotherapy for intestinal disease: using metabolites to prevent and treat disorders of the gut.
    Shan Liu, Marina Domingo-Vidal, Bhoomi Madhu, Dana Binyamin, Christoph A Thaiss, Maayan Levy.
      The gastrointestinal tract harbours a vast chemical diversity of small molecules, consisting of dietary nutrients, microorganism-derived metabolites and metabolic products of the host. The latest evidence highlights a direct involvement of different metabolites in the diverse aetiologies of intestinal diseases, ranging from inflammatory to metabolic and neoplastic conditions. The accessibility of the gastrointestinal tract to oral intervention suggests that fine-tuning the levels of intestinal metabolites might be a promising and currently underutilized therapeutic strategy. Here, we provide a conceptual overview of the recurring mechanistic themes by which metabolites shape the biology of immune cells, epithelium and neurons of the gastrointestinal tract. Additionally, we classify metabolites according to possible categories of therapeutic intervention, and summarize the latest preclinical and clinical data unveiling the roles of intestinal metabolites in the pathophysiology of major diseases of the gastrointestinal tract, including inflammatory bowel disease, irritable bowel syndrome, colorectal cancer, enteric infection, food allergy, coeliac disease, as well as obesity and metabolic syndrome. In each case, we provide an overview of the mechanisms by which intestinal metabolites have been associated with disease aetiology. In addition, we discuss possible metabolite-based strategies for intervention. Our overall goal is to provide a roadmap towards developing metabotherapies for intestinal disease.
    DOI:  https://doi.org/10.1038/s41575-026-01178-9
  11. Cancer Control. 2026 Jan-Dec;33:33 10732748261432271
    The Increase of Early-Onset Colorectal Cancer: New Insights and Emerging Hypotheses.
    Isaac Lee, Ezra Bernstein, Benjamin Lebwohl, Alfred I Neugut.
      Rising rates of early-onset colorectal cancer have been noted worldwide. This commentary addresses possible causes of this trend and opportunities for intervention.
    Keywords:  colonoscopy; colorectal cancer; colorectal cancer screening; early-onset colorectal cancer; fecal immunochemical test; fecal occult blood test
    DOI:  https://doi.org/10.1177/10732748261432271
  12. Nature. 2026 Mar 03.
    Genetically encoded assembly recorder temporally resolves cellular history.
    Yuqing Yan, Jiaxi Lu, Zhe Li, Zuohan Zhao, Timothy F Shay, Shunzhi Wang, Yaping Lei, Yimei Wang, Wei Chen, Patrick Parker, Hongru Yang, Aileen Qi, Yongzhi Sun, Dwight E Bergles, David Baker, Dingchang Lin.
      Cells constantly change their molecular state in response to internal and external cues1. Mapping cellular activity in tissues with spatiotemporal precision is essential for understanding organ physiology, pathology, and regenerative processes. Current cell-sensing modalities primarily rely on either endpoint analysis that takes static snapshots, or real-time sensing that monitors a small subset of cells3,4. Here, we introduce Granularly Expanding Memory for Intracellular Narrative Integration (GEMINI), an in cellulo recording platform that leverages a computationally designed protein assembly as an intracellular memory device to record the history of individual cells. GEMINI grows predictably within live cells, capturing cellular events as tree-ring-like fluorescent patterns for imaging-based retrospective readout. Absolute chronological information of activity histories is attainable with hour-level accuracy. GEMINI effectively maps differential NFκB-mediated transcriptional changes, resolving fast dynamics of 15 minutes and providing quantifiable signal amplitudes. In a xenograft model, GEMINI records inflammation-induced signaling dynamics across tissue, revealing spatial heterogeneity linked to vascular density. When expressed in the mouse brain, GEMINI minimally impacts neuronal functions and can resolve both transcriptional changes and activity patterns of neurons. Together, GEMINI provides a robust and generalizable means for spatiotemporal mapping of cell dynamics underlying physiological and pathological processes in both culture and intact tissues.
    DOI:  https://doi.org/10.1038/s41586-026-10323-y
  13. Med Oncol. 2026 Mar 04. pii: 167. [Epub ahead of print]43(4):
    A different perspective on the cancer stem cell theory.
    Arezu Karimpur-Zahmatkesh, Mohammad Khalaj-Kondori.
      Increased recurrence risk, aggressiveness, metastasis, and poor prognosis of cancer disease are challenges of conventional cancer treatment strategies attributed to cancer stem cells (CSCs). These cells are primarily defined as a small number of cancer cells with stemness potency. They are known to be the potential cause of conventional anticancer therapy resistance, including chemo-radiotherapy or hormonal reagents that can self-renew, remain dormant for an extended period, and, in doing so, promote tumor growth. CSC's theory presents possible causes of disease relapse after successful conventional therapies. Removing these stem cells seems logical to optimize the outcomes of related therapeutic strategies. Comprehensively identifying the evolutionary path and biology of cancer cells and supposed CSCs can direct us towards appropriate management of the disease. In the current study, we discuss recent findings that present clues to reshape our understanding of cancer stem cell theory and portray a novel perspective on cancer cell evolution and potential cancer stem cells (CSCs). Although there is a need for more in-depth studies in this area, current theory can alter therapeutic options and disease control methods. It may lead to a revolution in oncology science.
    Keywords:  Cancer; Cancer stem cell; Evolutionary pathway; Origin; Theory
    DOI:  https://doi.org/10.1007/s12032-025-03224-z
  14. Nat Methods. 2026 Mar 02.
    DECODE: deep learning-based common deconvolution framework for various omics data.
    Tianyi Zhao, Renjie Liu, Yuzhi Sun, Bingtian Wang, Liyuan Zhang, Qiuhao Chen, Ruibang Luo, Zhiyuan Yuan, Guohua Wang, Liang Cheng, Yadong Wang.
      Deconvolution algorithms estimate cell-type abundances from tissue-level data, enabling systematic cellular analysis of large cohorts. However, most deconvolution algorithms are specifically designed for single-omics data, thereby limiting their generalizability and scalability for various omics data from different cohorts. Here we present DECODE, a universal deconvolution framework for both cell types and cell states that can be applied to transcriptomic, proteomic and metabolomic data, and that seamlessly integrates diverse multiomics tissue datasets at the cellular level. DECODE fills the gap in metabolomics deconvolution and significantly outperformed state-of-the-art methods on different omics data across donors, disease conditions, healthy states, datasets and measurement platforms. In addition, DECODE exhibits high robustness in scenarios that are closer to real applications so it can accurately deconvolve known cell types even when the reference single-cell data are incomplete. DECODE will serve as a powerful tool for the fully extending multiomics cohort data into cellular level.
    DOI:  https://doi.org/10.1038/s41592-026-03007-y
  15. Nat Microbiol. 2026 Mar 06.
    Spatial transcriptomics maps host-gut microbiome biogeography at high resolution.
    Ioannis Ntekas, Lena Takayasu, David W McKellar, Benjamin Grodner, Chase Holdener, Peter Schweitzer, Young Seo Park, Maya Sauthoff, Qiaojuan Shi, Ilana L Brito, Iwijn De Vlaminck.
      Intermicrobial and host-microbial interactions are critical for the functioning of the gut microbiome, but few tools are available to measure these interactions in situ. Here we report a method for broad spatial sampling of microbiome-host interactions in the gut at high resolution (1 µm). This method combines enzymatic in situ polyadenylation of both bacterial and host RNA with spatial RNA sequencing to increase bacterial RNA recovery and enable transcriptomic analysis of low-abundance and spatially restricted microbial taxa. We benchmark the method against existing spatial transcriptomic workflows, demonstrating improved sensitivity and resolution. Application of this method in a mouse model of intestinal neoplasia revealed the biogeography of the mouse gut microbiome as function of location in the intestine, frequent strong intermicrobial interactions at short length scales and tumour-associated changes in the architecture of the host-microbiome interface. This method is compatible with widely available commercial platforms for spatial RNA sequencing and can therefore be readily adopted to study the role of short-range, bidirectional host-microbe interactions in microbiome health and disease.
    DOI:  https://doi.org/10.1038/s41564-026-02286-7
  16. Cancer Discov. 2026 Feb 06. OF1
    Bringing AI to Cancer's Regulatory Genome.
      A new AI model that predicts how noncoding DNA mutations alter gene regulation is helping cancer researchers identify which genetic changes drive tumor initiation and progression. Early studies show how AlphaGenome can unify multiple layers of genomic regulation into a single framework, accelerating the discovery of cancer-relevant mutations that previously required years of experimental work to decipher.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NW2026-0011
  17. Nat Genet. 2026 Mar 02.
    Harnessing genomics for early cancer detection, risk stratification and prevention.
    Muxin Gu, Woody Z Zhang, Rebecca C Fitzgerald, Alexander M Frankell, George S Vassiliou.
      Therapeutic advances have improved cancer outcomes, but early-stage detection remains the single most important determinant of favorable prognoses across many cancer types. Cancer genomics has yielded detailed maps of somatic mutation and methylation patterns characteristic of different cancers, enabling the development of assays to detect mutation-bearing tumor-derived DNA in tissue biopsies, blood and other body fluids at the earliest stages of disease. In parallel, it has also become clear that small clones bearing cancer-associated mutations arise commonly in histologically normal tissues, a phenomenon that becomes universal in proliferative tissues with age but leads to cancer in only a small minority of individuals. This review article outlines established strategies for early cancer detection and highlights emerging insights into the genetics of precancerous mutant clones that have led to the recent development of prognostic frameworks for identifying high-risk individuals, making it increasingly possible to intercept evolving cancer at a premalignant or early malignant stage, when interventions are most effective.
    DOI:  https://doi.org/10.1038/s41588-026-02505-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒03‒15 at 20:56.