bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–01–11
thirty papers selected by
Xiao Qin, University of Oxford
  1. Integrated Microfluidic Platform for High-Throughput Generation of Intestinal Organoids in Hydrogel Droplets.
  2. Computational generation of high-content digital organs at single-cell resolution.
  3. Cell stiffness regulates immune evasion during metastatic dormancy.
  4. Precancerous microenvironment: A signalling perspective.
  5. Decoding cell state transitions driven by dynamic cell-cell communication in spatial transcriptomics.
  6. The Next Chapter of Cancer Immunology Research.
  7. Framework for cancer evolution profiling and interception in colorectal cancer: ASCEND-CRC program.
  8. Bidirectional CRISPR screens decode a GLIS3-dependent fibrotic cell circuit.
  9. Exploiting tumor lineage features for precision cancer therapy.
  10. A Tissue Renewal-Based Mechanism Drives Colon Tumorigenesis.
  11. Colon Organoids as Experimental Models to Study the Effect of Micro-Nanoparticles as a Driver of Early-Onset Colon Cancer.
  12. Whole-genome spatial transcriptomic imaging with RAEFISH.
  13. Proteoform medicine: characterizing and targeting protein forms in human disease.
  14. Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.
  15. The Need for a Systems Biology Approach in Cancer Explained.
  16. Tight junction-high and CDH17-positive cell population is the source of colorectal cancer liver metastases.
  17. CausalGRN: deciphering causal gene regulatory networks from single-cell CRISPR screens.
  18. Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial-immune cell interactions.
  19. Learning to lead.
  20. Why cancer can come back years later - and how to stop it.
  21. Dictionary of human intestinal organoid responses to secreted niche factors at single cell resolution.
  22. Machine learning-based multimodal biomarkers enable accurate diagnosis and early detection of pancreatic ductal adenocarcinoma.
  23. The gut microbiome in colorectal cancer: mechanisms of carcinogenesis and emerging microbiota-targeted therapies.
  24. Value of Stool-Based Colorectal Cancer Screening: Integrating Real-World Adherence, Detection, and Prevention in a Cohort-Based Modeling Analysis.
  25. An expanded registry of candidate cis-regulatory elements.
  26. TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis.
  27. Mapping the disease interactome.
  28. Opportunities and challenges of targeting cGAS-STING in cancer.
  29. A guide to cancer screening.
  30. A targeted DNA methylation method for detecting gastrointestinal cancer in circulating cell-free DNA.
  1. Adv Sci (Weinh). 2026 Jan 05. e16507
    Integrated Microfluidic Platform for High-Throughput Generation of Intestinal Organoids in Hydrogel Droplets.
    Barbora Lavickova, Hannah Kronabitter, Mar Cervera-Negueruela, Eylul Ceylan, Laura Benito-Zarza, Rubén López-Sandoval, Irineja Cubela, J Gray Camp, Jose L Garcia-Cordero.
      Organoid research offers valuable insights into human biology and disease, but reproducibility and scalability remain significant challenges, particularly for epithelial organoids. Here, we present an integrated microfluidic platform that addresses these limitations by enabling high-throughput generation of uniform hydrogel microparticles embedded with primary-derived human adult intestinal stem cells. Our platform includes a cell distribution system for homogeneous cell encapsulation and a microfluidic oil-removal module for efficient particle transfer to aqueous media. We demonstrate the successful culture and differentiation of both healthy- and tumor-derived intestinal organoids within these microparticles, achieving high homogeneity and reproducibility. This integrated microfluidic approach holds promise for scalable and standardized organoid production, with potential applications in drug screening, disease modeling, and personalized medicine. encapsulation; high-throughput; hydrogels; microfluidics; organoids.
    DOI:  https://doi.org/10.1002/advs.202516507
  2. Nat Methods. 2026 Jan 06.
    Computational generation of high-content digital organs at single-cell resolution.
      
    DOI:  https://doi.org/10.1038/s41592-025-02996-6
  3. Nat Cancer. 2026 Jan 05.
    Cell stiffness regulates immune evasion during metastatic dormancy.
    Andrea Pérez González, Cédric Blanpain.
      
    DOI:  https://doi.org/10.1038/s43018-025-01096-w
  4. Curr Opin Cell Biol. 2026 Jan 07. pii: S0955-0674(25)00149-8. [Epub ahead of print]98 102611
    Precancerous microenvironment: A signalling perspective.
    Xiao Qin.
      The progression from healthy tissue to malignancy involves a critical precancerous stage marked by cellular lesions with aberrant molecular and phenotypic characteristics. The fate of these lesions is shaped not only by cell-intrinsic alterations but also by the precancerous microenvironment (PME), an ecosystem of epithelial, stromal and immune cells embedded within the extracellular matrix. Focusing on epithelial precancers, this review first defines the metastable state and signalling networks that distinguish precancer from homeostasis and cancer. It then examines the models and technologies used to investigate PME signalling across spatial-temporal dimensions, followed by an integrated overview of how PME components collectively shape lesion trajectories. Finally, it outlines the outstanding questions and research priorities needed to advance mechanistic insight and realise the translational potential of PME-targeted interventions.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102611
  5. Nat Comput Sci. 2026 Jan 05.
    Decoding cell state transitions driven by dynamic cell-cell communication in spatial transcriptomics.
    Lulu Yan, Dongyan Zhang, Xiaoqiang Sun.
      In multicellular systems, cell fate determination emerges from the integration of intracellular signaling and intercellular communication. Spatial transcriptomics (ST) provides opportunities to elucidate these regulatory processes, yet inferring the spatiotemporal dynamics of cell state transitions (CSTs) governed by cell-cell communication (CCC) remains a challenge. Here we introduce CCCvelo to reconstruct CCC-driven CST dynamics by jointly optimizing a dynamic CCC signaling network and a latent CST clock. CCCvelo formulates a unified multiscale nonlinear kinetic model that integrates intercellular ligand-receptor signaling gradients with intracellular transcription-factor activation cascades to capture gene expression dynamics encoding CSTs. Moreover, we devise PINN-CELL, a physics-informed neural-network-based coevolution learning algorithm, which simultaneously optimizes model parameters and pseudotemporal ordering. Application of CCCvelo to high-resolution ST datasets, including mouse cortex, embryonic trunk development and human prostate cancer datasets, demonstrates its ability to successfully recover known morphogenetic trajectories while uncovering dynamic CCC signaling rewiring that orchestrates CST progression.
    DOI:  https://doi.org/10.1038/s43588-025-00934-2
  6. Cancer Immunol Res. 2026 Jan 08. 14(1): 8-9
    The Next Chapter of Cancer Immunology Research.
    Elizabeth M Jaffee, Antoni Ribas.
      
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1391
  7. Cancer Cell. 2026 Jan 08. pii: S1535-6108(25)00550-1. [Epub ahead of print]
    Framework for cancer evolution profiling and interception in colorectal cancer: ASCEND-CRC program.
    Salvador Alonso, Kanwal Raghav, Van K Morris, Kristin Alfaro-Munoz, Tanios Bekaii-Saab, Timothy L Cannon, Ryan B Corcoran, Nicholas Duesbery, Manju George, David Hsu, Christopher Lieu, Anirban Maitra, Dipen Maru, Jasmine A McQuerry, David Menter, Jonathan Mizrahi, Kimmie Ng, Aparna Parikh, Kunal Rai, Michelle C Sangar, Kenna R Shaw, John Paul Shen, John H Strickler, Ann D Feehan, Alda L Tam, Guglielmo Vetere, Rona Yaeger, Ying Yuan, Xiling Shen, Andrea H Bild, Scott Kopetz.
      Cancer evolution is a complex and dynamic process, yet most treatment strategies remain static. Infrequent tumor sampling has limited our ability to counteract the transient adaptive states that precede resistance. To address this gap, ARPA-H launched the ADAPT program, an initiative aimed at transforming cancer care by aligning therapies with real-time tumor evolution. Within this framework, the ASCEND-CRC trial aims to uncover early adaptive mechanisms and identify biomarkers to guide therapeutic decision-making in metastatic colorectal cancer (CRC). The study moves beyond single pre-treatment biomarkers by integrating multimodal profiling to longitudinally track tumor evolution and define an actionable set of dynamic biomarkers that inform treatment decisions. Together with other ADAPT initiatives, ASCEND-CRC represents a paradigm shift in precision oncology, establishing a scalable platform to intercept resistance.
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.016
  8. Nature. 2026 Jan 07.
    Bidirectional CRISPR screens decode a GLIS3-dependent fibrotic cell circuit.
    Vladislav Pokatayev, Alok Jaiswal, Angela R Shih, Åsa Segerstolpe, Bihua Li, Elizabeth A Creasey, Yanhua Zhao, Crystal Lin, Shane Murphy, Chih-Hung Chou, Daniel B Graham, Ramnik J Xavier.
      The stromal cell compartment plays a central part in the maintenance of tissue homeostasis by coordinating with the immune system throughout inception, amplification and resolution of inflammation1. Chronic inflammation can impede the phased regulation of tissue restitution, resulting in the scarring complication of fibrosis. In inflammatory bowel disease, stromal fibroblasts have been implicated in treatment-refractory disease and fibrosis2,3; however, their mechanisms of activation have remained undefined. Through integrative single-cell and spatial profiling of intestinal tissues from patients with inflammatory bowel disease, we uncovered a pathological cell nexus centred on inflammation-associated fibroblasts. These fibroblasts were induced by proinflammatory macrophages (FCN1+IL1B+) and, in turn, produced profibrotic cytokine IL-11. We investigated the inflammation-associated fibroblast activation program at a mechanistic level using genome-wide CRISPR knockout and activation screens and identified the transcription factor GLIS3 as a key regulator of a gene regulatory network governing expression of inflammatory and fibrotic genes. We further demonstrated that the magnitude of the GLIS3 gene expression program in intestinal biopsies could be used to stratify patients with ulcerative colitis by disease severity, and that fibroblast-specific deletion of Glis3 in mice alleviated pathological features of chronic colitis. Taken together, our findings identify a critical immune-stromal cell circuit that functions as a central node in the inflammation-fibrosis cycle.
    DOI:  https://doi.org/10.1038/s41586-025-09907-x
  9. Trends Cancer. 2026 Jan 02. pii: S2405-8033(25)00311-5. [Epub ahead of print]
    Exploiting tumor lineage features for precision cancer therapy.
    Lois M Kelly, Nina Fenouille, Kris C Wood, Alexandre Puissant.
      Cancer cells often retain lineage- and tissue of origin-specific programs established prior to malignant transformation. This observation has been elaborated by advances in single-cell and lineage-tracing technologies, which provide high-resolution mapping of these features. Here, we provide an overview of these recent technological developments and examine how the tissue of origin shapes tumor behavior and vulnerabilities. We discuss how the preferential selection of oncogenic drivers by specific tissues leads to distinct genetic alterations across cancers. We then explore the continued dependence of cancer cells on lineage-specific physiological functions and signaling pathways, thereby revealing lineage-dependent therapeutic targets. Finally, we highlight how lineage-specific cell surface marker expression informs precision immunotherapies. Together, these insights are driving a shift toward therapies tailored to the developmental and functional identities of cancer cells.
    Keywords:  cancer specialized function; high-resolution mapping; lineage dependencies; lineage-tracing systems; precision oncology; targeted therapies; tissue-selective oncogenic drivers; tumor antigen repertoire for advanced T cell therapies; tumor tissue of origin
    DOI:  https://doi.org/10.1016/j.trecan.2025.12.004
  10. Cancers (Basel). 2025 Dec 23. pii: 44. [Epub ahead of print]18(1):
    A Tissue Renewal-Based Mechanism Drives Colon Tumorigenesis.
    Ryan M Boman, Gilberto Schleiniger, Christopher Raymond, Juan Palazzo, Anne Shehab, Bruce M Boman.
      Our Goal is to identify how colorectal cancer (CRC) arises in the single-layered cell epithelium (simple columnar epithelium) that lines the luminal surface of the large intestine. Background: We recently reported that the dynamic organization of cells in colonic epithelium is encoded by five biological rules and conjectured that colon tumorigenesis involves an autocatalytic tissue renewal reaction. Introduction Our objective was to define how altered crypt turnover explains tissue disorganization that leads to adenoma morphogenesis and CRC. Hypothesis: Changes in rate of tissue renewal-based cell polymerization leads to epithelial expansion and tissue disorganization during adenoma histogenesis. Methods: Accordingly, we created a computational model that considers the structure of colonic epithelium to be a polymer of cells and that tissue renewal is autocatalytic. Indeed, self-renewal of stem cells in colonic crypts continuously produces cells that act like monomers to form a polymer of cells (an interconnected, continuous cell sheet) in a polymerization-based process. Our model is a system of nonlinear differential equations that simulates changes in human crypt cell population dynamics. Results: We investigated how changes occur in the proportion of different cell types during adenoma development in FAP patients. The results show premalignant colonic crypts have a decreased rate of tissue renewal due to APC-mutation. Discussion: This slower rate of cell polymerization causes a rate-limiting step in the crypt renewal process that expands the proliferative cell population size. Conclusions: Our findings provide a mechanism that explains how a prolonged rate of crypt renewal leads to tissue disorganization with local epithelial expansion, infolding, and contortion during adenoma morphogenesis.
    Keywords:  APC gene; colorectal cancer; familial adenomatous polyposis; systems biology; tissue renewal
    DOI:  https://doi.org/10.3390/cancers18010044
  11. Cells. 2025 Dec 25. pii: 40. [Epub ahead of print]15(1):
    Colon Organoids as Experimental Models to Study the Effect of Micro-Nanoparticles as a Driver of Early-Onset Colon Cancer.
    Zahra Heydari, Gobinda Sarkar, Lauren Helgeson, Estela Mariel Cruz Garcia, Alexandra Ros, Khashayarsha Khazaie, Lisa Boardman.
      Early-onset colorectal cancer (EOCRC) in people < 50 years of age has been rising globally, yet its causes remain unknown. Emerging evidence suggests that environmental factors, including exposure to micro-and nanoplastics (MNPs), may contribute to colorectal carcinogenesis. MNPs can enter the gastrointestinal tract through ingestion, translocate across the epithelial barrier via endocytosis or paracellular pathways, and interact directly with epithelial and immune cells. Once internalized, they may generate events associated with tumor initiation including oxidative stress, disruption of membrane integrity, pro-inflammatory signaling, and disruption of genomic and epigenomic stability. Patient-derived colorectal organoids offer a physiologically relevant and scalable 3D model that closely mimics the cellular architecture and genetic landscape of primary tumors. We highlight how organoid models can be leveraged to study the impact of MNPs on the key processes of inflammation, DNA damage, senescence, and epigenetic modifications. Furthermore, we discuss the application of organoid-based systems to model EOCRC driven by environmental exposures, including the integration of organoid platforms with high-throughput assays, omics profiling, and microfluidics to better capture MNP-induced pathogenic mechanisms. Altogether, colorectal organoids provide a powerful bridge between environmental plastic exposure and EOCRC etiology, offering a tractable platform to identify mechanistic pathways and potential biomarkers of early disease.
    Keywords:  colorectal cancer; early-onset CRC; micro- and nanoplastics; organoid
    DOI:  https://doi.org/10.3390/cells15010040
  12. Nat Rev Genet. 2026 Jan 09.
    Whole-genome spatial transcriptomic imaging with RAEFISH.
    Yubao Cheng.
      
    DOI:  https://doi.org/10.1038/s41576-025-00926-y
  13. Nat Rev Genet. 2026 Jan 05.
    Proteoform medicine: characterizing and targeting protein forms in human disease.
    Jennifer A Korchak, S Stephen Yi, Neil L Kelleher, Nidhi Sahni, Gloria M Sheynkman.
      Proteoforms are the diverse molecular protein species produced from a single gene through genetic variation, alternative splicing and post-translational modifications. They are the crucial link between genotype and phenotype. There are estimated to be more than one million distinct protein variants produced from ~20,000 protein-coding genes in a given cell, making these proteoforms a vast and largely uncharacterized dimension in biomedical research. This Review focuses on the role of proteoforms in human genetic diseases. We highlight cutting-edge technologies for the identification and characterization of proteoforms, including long-read transcriptomics and emerging methods for direct protein sequencing, and we present a network biology framework to explain how proteoforms can perturb the molecular interactions and cellular pathways underlying disease phenotypes. We believe that precision medicine will require precision proteomics. An increasing knowledge of proteoform biology from molecular, systems and clinical perspectives will guide future research, ultimately contributing to a more precise understanding of the molecular basis of disease and refined therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41576-025-00915-1
  14. Proc Natl Acad Sci U S A. 2026 Jan 13. 123(2): e2515183123
    Systematic identification of single transcription factor perturbations that drive cellular and tissue rejuvenation.
    Janine Sengstack, Jiashun Zheng, Turan Aghayev, Gregor Bieri, Michael Mobaraki, Jue Lin, Changhui Deng, Saul A Villeda, Hao Li.
      Cellular rejuvenation through transcriptional reprogramming is an exciting approach to counter aging. Using a fibroblast-based model of human cell aging and Perturb-seq screening, we developed a systematic approach to identify single transcription factor (TF) perturbations that promote rejuvenation without dedifferentiation. Overexpressing E2F3 or EZH2, and repressing STAT3 or ZFX, reversed cellular hallmarks of aging-increasing proliferation, proteostasis, and mitochondrial activity, while decreasing senescence. EZH2 overexpression in vivo rejuvenated livers in aged mice, reversing aging-associated gene expression profiles, decreasing steatosis and fibrosis, and improving glucose tolerance. Mechanistically, single TF perturbations led to convergent downstream transcriptional programs conserved in different aging and rejuvenation models. These results suggest a shared set of molecular requirements for cellular and tissue rejuvenation across species.
    Keywords:  Perturb-seq screening; liver aging; rejuvenation; replicative aging
    DOI:  https://doi.org/10.1073/pnas.2515183123
  15. Int J Mol Sci. 2025 Dec 22. pii: 141. [Epub ahead of print]27(1):
    The Need for a Systems Biology Approach in Cancer Explained.
    Hehuan Zhu, Xi Zhang, Ehsan Nazemalhosseini-Mojarad, Jessica Roelands, Lysanne D A N de Muynck, Cor J Ravensbergen, Rachel Hoorntje, Imke Stouten, Marianne Hokland, Alexander L Vahrmeijer, Rob A E M Tollenaar, Edwin Koster, Peter J K Kuppen.
      Traditionally, scientists tend to approach cancer research in a reductionistic way: aiming at uncovering underlying, separate components in malignant processes. And indeed, great progress has been made by reducing the development of a tumor to single, specific genes and mutations. For instance, familial adenomatous polyposis (FAP) could be reduced to a germline mutation in the Adenomatous Polyposis Coli (APC) gene. The escape of tumor cells from immune surveillance could be reduced to the tumor expression of immune checkpoints, resulting in new approaches in tumor therapy by applying immune checkpoint inhibitors. However, a germline mutation in APC is not 1:1 related to colorectal cancer (CRC), and only some patients respond to immune checkpoint inhibitors. The point here is that biological systems, also comprising cancer, have properties that cannot be reduced to single components. The cooperation of the single components results in new, emergent properties. The outcome of an interaction in a complex network, like the immune system, depends on the many cell types involved and the numerous molecules that interact and activate or inhibit pathways. The way the composing elements are organized is a causal factor in itself for any emergent property. The rise of genomic analysis at the end of the previous century, enabling us to sequence a full genome at the DNA and RNA levels, has initiated an awareness of the need for 'systems biology': to consider a full system and how it is organized, in all of its aspects, to understand biological pathways and their outcomes. In this review, we outline the prospects and limitations of systems biology in cancer research and propose a causal framework that integrates upward and downward causation and multiple realizability to understand the emergent properties of tumors that determine the dynamics of tumor development.
    Keywords:  cancer; downward causation; emergent property; molecular biology; systems biology; upward causation
    DOI:  https://doi.org/10.3390/ijms27010141
  16. Nat Commun. 2026 Jan 03.
    Tight junction-high and CDH17-positive cell population is the source of colorectal cancer liver metastases.
    Daniel Alvarez-Villanueva, María Maqueda, Dina Harti, Eric Canton, Evelyn Andrades, Joan Bertran, María Martínez-Iniesta, Laura Solé, Violeta García-Hernández, Ángela Montoto, Teresa Lobo-Jarne, Josune Alonso-Marañón, Patricia Herrero-Molinero, Mónica Larrubia-Loring, Anna Tramuns, Kieran Wynne, Indrani Bera, David Matallanas, Alberto Villanueva, Anna Bigas, Mar Iglesias, Lluís Espinosa.
      Colorectal cancer (CRC) frequently develops aggressive metastatic disease, yet the cellular features that enable dissemination remain poorly defined. IKKα, a kinase traditionally linked to stress and inflammatory signaling, is increasingly recognized for broader functions in cancer. Here, we show that loss of IKKα unexpectedly promotes metastasis in CRC. Using patient-derived organoids, we find that genetic or pharmacological inhibition of IKKα stabilizes tight-junction components, leading to the emergence of compact epithelial clusters with a heightened ability to spread and colonize the liver. Single-cell transcriptomics reveals expansion of a CDH17⁺/CLDN2⁺ epithelial subpopulation that dominates metastatic lesions, a finding validated by tissue staining. Remarkably, disrupting CLDN2 completely eliminates the metastatic advantage caused by IKKα loss. These results identify a metastasis-competent epithelial state driven by tight-junction remodeling and uncover a vulnerable node that may be exploited therapeutically in aggressive colorectal cancer.
    DOI:  https://doi.org/10.1038/s41467-025-68169-3
  17. bioRxiv. 2025 Dec 31. pii: 2025.12.30.692369. [Epub ahead of print]
    CausalGRN: deciphering causal gene regulatory networks from single-cell CRISPR screens.
    Bo Yu, Dingyu Liu, Guanghao Qi, Danwei Huangfu, Li Hsu, Ali Shojaie, Wei Sun.
      Large-scale single-cell CRISPR screens with single-cell RNA-seq (scRNA-seq) readouts provide critical data to map causal gene regulatory networks (GRNs). However, translating the complex scRNA-seq outputs into reliable causal insights remains a major analytical challenge. Here we present CausalGRN, a scalable computational framework that infers causal GRNs and predicts cellular responses to unseen perturbations. CausalGRN first mitigates pervasive spurious partial correlations in sparse scRNA-seq data through a novel adaptive thresholding correction, enabling robust inference of an undirected graph. It then orients this graph using observed perturbation outcomes. The resulting directed GRN can be used to predict the downstream effects of novel perturbations via network propagation. Across both simulations and diverse experimental datasets, CausalGRN substantially outperforms existing approaches in network reconstruction accuracy and in predicting the effects of unseen perturbations, providing a principled bridge from perturbation data to causal gene regulation.
    DOI:  https://doi.org/10.64898/2025.12.30.692369
  18. bioRxiv. 2025 Dec 23. pii: 2025.12.22.695505. [Epub ahead of print]
    Diverse infections transcriptionally reprogram the intestinal epithelium and epithelial-immune cell interactions.
    MIST Consortium
      The distal small intestine plays vital roles in host physiology by regulating nutrient and fluid homeostasis. Despite being impacted in Crohn's disease and a major target for a range of infections, we know relatively little about the complexity of cellular responses and cell-cell communication in the ileum during infection. Single cell and spatial transcriptomics have emerged as powerful technologies to study tissue heterogeneity in the gut, but these tools have focused on the large intestine, in part due to the accessibility of this tissue for biopsies and its importance in cancer. Here we present GutPath, an atlas of over 500,000 single cells with RNA and protein expression profiles for 91 cell states in the ileum across diverse infectious archetypes. We show that GutPath accurately captures established immune responses to infection while revealing pathogen-specific responses in enterocytes. To highlight the discovery potential of this atlas, we identify a novel enterocyte cell state present during Yersinia pseudotuberculosis infection that is spatially linked to bacterial load and tissue pathology. GutPath establishes a much-needed resource for the immunology community that will accelerate the study of the transcriptional diversity of cellular landscapes in the small intestine.
    DOI:  https://doi.org/10.64898/2025.12.22.695505
  19. Science. 2026 Jan 08. 391(6781): 210
    Learning to lead.
    Derek O'Keeffe.
      
    DOI:  https://doi.org/10.1126/science.aef2259
  20. Nature. 2026 Jan;649(8096): 282-284
    Why cancer can come back years later - and how to stop it.
    Amanda Heidt.
      
    Keywords:  Cancer; Cell biology; Diseases; Drug discovery
    DOI:  https://doi.org/10.1038/d41586-025-04149-3
  21. Nat Commun. 2026 Jan 09.
    Dictionary of human intestinal organoid responses to secreted niche factors at single cell resolution.
    Meghan M Capeling, Bob Chen, Kazeera Aliar, Elisa Penna, Veronica Ibarra Lopez, Conrad Foo, Sandra Rost, Loryn Holokai, Xinming Tong, Devan Phillips, Caden Sweet, Jing Li, Sharmila Chatterjee, Elizabeth Skippington, Zora Modrusan, Lisa M McGinnis, Runmin Wei, Mary Keir, Orit Rozenblatt-Rosen, Michelle B Chen.
      The intestinal epithelium plays a critical role in health and disease, yet the impact of microenvironmental cues in diseased contexts, such as inflammatory bowel disease (IBD), remains poorly defined. To address this gap, we first benchmarked human colonic organoid injury models against IBD tissue and established a disease-relevant model of inflammation using inflammatory cytokines. Using this system, we built a dictionary of epithelial responses to 79 secreted niche factors at single cell resolution via donor-pooled, multiplexed single cell RNA-sequencing. The comprehensive nature of our atlas allowed us to map relationships between perturbations, infer the function of less characterized ligands, and identify cell type-specific perturbed pathways. Finally, we established the relevance of organoid-derived gene programs by mapping them to single cell and spatial atlases of human IBD tissue. Our resource offers a global view of epithelial responses to microenvironmental cues, offering insights into epithelial homeostasis and repair mechanisms in IBD.
    DOI:  https://doi.org/10.1038/s41467-025-68247-6
  22. Sci Rep. 2026 Jan 07. 16(1): 658
    Machine learning-based multimodal biomarkers enable accurate diagnosis and early detection of pancreatic ductal adenocarcinoma.
    Tsung-Hung Yao, Warapen Treekitkarnmongkol, Nagireddy Putluri, Deivendran Sankaran, Tristian Nguyen, Seetharaman Balasenthil, Mark W Hurd, Meng Chen, Randall E Brand, Paul D Lampe, Abu Hena M Kamal, Vasanta Putluri, Tony Y Hu, Anirban Maitra, Eugene J Koay, Ann M Killary, Subrata Sen, Suprateek Kundu.
      
    Keywords:  Biomarkers; Early detection; Integrated multimodal analysis; Pancreatic adenocarcinoma
    DOI:  https://doi.org/10.1038/s41598-025-29548-4
  23. Discov Oncol. 2026 Jan 07.
    The gut microbiome in colorectal cancer: mechanisms of carcinogenesis and emerging microbiota-targeted therapies.
    Yue Li, Xingyu Shen, Deqiang Wang, Kang Sun.
      
    Keywords:  Carcinogenesis; Chemoresistance; Colorectal cancer; Fecal microbial transplantation; Microbiome
    DOI:  https://doi.org/10.1007/s12672-025-04367-1
  24. J Clin Med. 2025 Dec 20. pii: 41. [Epub ahead of print]15(1):
    Value of Stool-Based Colorectal Cancer Screening: Integrating Real-World Adherence, Detection, and Prevention in a Cohort-Based Modeling Analysis.
    A Mark Fendrick, Derek W Ebner, Michael Dore, Chris Estes, Gustavus Aranda, Mohammad Dehghani.
      Background/Objectives: Modeling analyses for colorectal cancer (CRC) screening focusing solely on the costs of screening do not fully capture the value of screening programs. We evaluated the clinical and economic effects of CRC stool-based screening tests, including impacts on cancer-related outcomes. Methods: A cohort-based decision-analytic cost-estimator model estimated outcomes for a single round of screening with next-generation multi-target stool DNA (ng mt-sDNA) test or fecal immunochemical test (FIT) from a US payer perspective. Undiagnosed cancers were assumed to become symptomatic (and detected) within 10 years. Clinical assumptions, advanced precancerous lesion and CRC prevalence, and test performance inputs were from clinical trial data. Adherence rates for initial screening and follow-up colonoscopy after a positive result were from real-world data. Input costs included the screening tests, follow-up colonoscopy (with and without polypectomy), and CRC treatment. Results: Compared with FIT, more individuals completed ng mt-sDNA (321,000 vs. 713,000, respectively), leading to the detection of more CRC cases (436 with FIT vs. 2235 with ng mt-sDNA), more advanced precancerous lesions, and more CRC at earlier stages. The cost of screening per patient screened was USD 801 for ng mt-sDNA and USD 124 for FIT. Follow-up colonoscopy cost was USD 149 million with ng mt-sDNA versus USD 22 million with FIT, whereas CRC treatment costs were lower for ng mt-sDNA (USD 1423 million versus USD 1474 million, respectively). When accounting for both direct and CRC averted costs, the total cost of screening and treatment was USD 1383 million with ng mt-sDNA versus USD 1427 million with FIT. Conclusions: Higher screening costs with ng mt-sDNA versus FIT are counterbalanced by savings realized from enhanced CRC prevention and earlier detection due to the superior test performance and better adherence with ng mt-sDNA.
    Keywords:  adherence; colorectal cancer; cost; screening; sensitivity; specificity; stool test
    DOI:  https://doi.org/10.3390/jcm15010041
  25. Nature. 2026 Jan 07.
    An expanded registry of candidate cis-regulatory elements.
    Jill E Moore, Henry E Pratt, Kaili Fan, Nishigandha Phalke, Jonathan Fisher, Shaimae I Elhajjajy, Gregory Andrews, Mingshi Gao, Nicole Shedd, Yu Fu, Matthew C Lacadie, Jair Meza, Mansi Khandpekar, Mohit Ganna, Eva Choudhury, Ross Swofford, Huong Phan, Christian C Ramirez, Maxwell Campbell, Mary Likhite, Nina P Farrell, Annika K Weimer, Anusri Pampari, Vivekanandan Ramalingam, Fairlie Reese, Beatrice Borsari, Xuezhu Yu, Eve Wattenberg, Marina Ruiz-Romero, Milad Razavi-Mohseni, Jinrui Xu, Timur Galeev, Andres Colubri, Michael A Beer, Roderic Guigó, Mark B Gerstein, Jesse M Engreitz, Mats Ljungman, Timothy E Reddy, Michael P Snyder, Charles B Epstein, Elizabeth Gaskell, Bradley E Bernstein, Diane E Dickel, Axel Visel, Len A Pennacchio, Ali Mortazavi, Anshul Kundaje, Zhiping Weng.
      Mammalian genomes contain millions of regulatory elements that control the complex patterns of gene expression1. Previously, the ENCODE consortium mapped biochemical signals across hundreds of cell types and tissues and integrated these data to develop a registry containing 0.9 million human and 300,000 mouse candidate cis-regulatory elements (cCREs) annotated with potential functions2. Here we have expanded the registry to include 2.37 million human and 967,000 mouse cCREs, leveraging new ENCODE datasets and enhanced computational methods. This expanded registry covers hundreds of unique cell and tissue types, providing a comprehensive understanding of gene regulation. Functional characterization data from assays such as STARR-seq3, massively parallel reporter assay4, CRISPR perturbation5,6 and transgenic mouse assays7 have profiled more than 90% of human cCREs, revealing complex regulatory functions. We identified thousands of novel silencer cCREs and demonstrated their dual enhancer and silencer roles in different cellular contexts. Integrating the registry with other ENCODE annotations facilitates genetic variation interpretation and trait-associated gene identification, exemplified by the identification of KLF1 as a novel causal gene for red blood cell traits. This expanded registry is a valuable resource for studying the regulatory genome and its impact on health and disease.
    DOI:  https://doi.org/10.1038/s41586-025-09909-9
  26. Nat Cancer. 2026 Jan 05.
    TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis.
    Zhenghan Wang, Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, Morgan Huse, Joan Massagué.
      Different forms of epithelial-to-mesenchymal transition (EMT) manifest during tumor progression. Little is known about the mechanistic basis and functional role of these distinct EMTs. We explored this question in lung adenocarcinoma (LUAD) primitive progenitors, which are competent to enter dormancy in response to transforming growth factor-β (TGFβ) upon metastatic dissemination. The TGFβ response in these cells includes growth arrest and a full EMT that subsequently transitions into an atypical mesenchymal state of round morphology and lacking actin stress fibers. TGFβ drives this transition by inducing expression of the actin depolymerizing protein gelsolin, which converts a migratory, stress-fiber-rich phenotype into a cortical actin-rich, spheroidal state. This transition lowers the biomechanical stiffness of metastatic progenitors and protects them from killing by cytotoxic lymphocytes. Gelsolin-deficient LUAD progenitors can enter dormancy but succumb to immune surveillance. Thus, quiescent LUAD metastatic progenitors undergo an atypical EMT to avert immune surveillance during TGFβ-driven metastatic dormancy.
    DOI:  https://doi.org/10.1038/s43018-025-01094-y
  27. Nat Rev Genet. 2026 Jan 05.
    Mapping the disease interactome.
    Valborg Gudmundsdottir.
      
    DOI:  https://doi.org/10.1038/s41576-025-00922-2
  28. Nat Rev Cancer. 2026 Jan 05.
    Opportunities and challenges of targeting cGAS-STING in cancer.
    Changzheng Lu, Wenyan Wang, Yang-Xin Fu.
      The cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway has a crucial role in detecting tumour-derived DNA, whether the pathway is generated spontaneously or induced therapeutically. Activation of the cGAS-STING pathway triggers type I interferon signalling and pro-inflammatory responses in both tumour and immune cells, establishing a delicate balance between pathological inflammation and protective immune responses. Although preclinical studies have highlighted the promise of targeting the cGAS-STING pathway to enhance antitumour immunotherapy, clinical results have fallen short of expectations. In this Review, we outline key advances in understanding the tumour-promoting and tumour-suppressive effects mediated by the cGAS-STING pathway and discuss opportunities and challenges for its integration into future cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41568-025-00894-9
  29. Nat Rev Clin Oncol. 2026 Jan 07.
    A guide to cancer screening.
    Stephen W Duffy, Judith Offman.
      The aim of cancer screening is to identify pre-malignant conditions, which can be removed or treated, or earlier-stage disease, for which treatment is more likely to be curative, in non-symptomatic individuals. Currently, screening programmes are being consolidated for five cancer types (breast, prostate, cervical, colorectal and lung) and several other cancer types are the focus of specific initiatives. Cancer screening is at a point of potential major transformation owing to technological advances in detection. In this Review, we first recapitulate the general principles of cancer screening. We then provide a timely overview of the current screening practices for breast, cervical, colorectal, prostate and lung cancer, addressing major challenges and potential future changes in practice. We also discuss other malignancies for which screening initiatives might be worth considering. Finally, we highlight technological developments in cancer detection that might hold promise for screening an increasing number of cancers in the future, notably some that reflect unmet needs.
    DOI:  https://doi.org/10.1038/s41571-025-01112-z
  30. iScience. 2026 Jan 16. 29(1): 114342
    A targeted DNA methylation method for detecting gastrointestinal cancer in circulating cell-free DNA.
    Zhaoyu Jiang, Yuqing Guo, Yongqu Lu, Kun Qian, Xiaomeng Liu, Siyi Lu, Jie Ren, Fuchou Tang, Wei Fu, Lu Wen, Xin Zhou.
      Colorectal cancer (CRC) and gastric cancer (GC) are leading causes of cancer-related mortality. However, cost-effective methods for simultaneous detection of CRC and GC in circulating cell-free DNA (cfDNA) remain insufficiently explored. To address this, we developed targeted methylated CpG tandem amplification and sequencing (tMCTA-seq), a PCR-based method utilizing a set of locus-specific primers with a universal CGCGCGG primer, and targeted a panel of 110 loci. The method demonstrated high technical sensitivity below one haploid genome equivalent. Using a repeated nested cross-validation framework, the ensemble model, applied to 448 plasma samples (170 CRC, 101 GC, and 177 control participants), achieved areas under the curve (AUCs) of 0.928 (88.2% sensitivity and 90.7% specificity) for CRC and 0.926 (86.7% sensitivity and 94.4% specificity) for GC on the test set. Furthermore, tMCTA-seq differentiated between CRC and GC (AUC = 0.819). Thus, tMCTA-seq is a cost-effective, methylation-based approach for simultaneous detection of and differentiation between two major gastrointestinal cancers in blood.
    Keywords:  Biochemistry; Cancer
    DOI:  https://doi.org/10.1016/j.isci.2025.114342
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