bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–07–05
thirteen papers selected by
Xiao Qin, University of Oxford
  1. Transcription regulation of cell fate plasticity - from embryonic development to tissue regeneration.
  2. Spatio-DARLIN enables robust and efficient in situ lineage tracing in mice at single-cell resolution.
  3. Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning.
  4. Imaging the hallmarks of cancer.
  5. TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer.
  6. Lineage tracing from cellular heritage to disease destiny.
  7. Spatially Resolved Proteomic Cartography Illuminates the Earliest Molecular Programs in Pancreatic Cancer Evolution.
  8. Patterns in motion: Choreographing dynamic cell behaviours during tissue repair.
  9. Ecology of the gut microbiome.
  10. Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex.
  11. A genome-scale CRISPRi perturbation atlas of human induced pluripotent stem cells.
  12. Daily briefing: Editing the epigenome with CRISPR to treat disease.
  13. A guide to CAR T cell therapies: development, current status and future prospects.
  1. Curr Opin Genet Dev. 2026 Jun 27. pii: S0959-437X(26)00074-2. [Epub ahead of print]100 102507
    Transcription regulation of cell fate plasticity - from embryonic development to tissue regeneration.
    Wenying Zhao, Xiao Huang, Congling Xu.
      Cell fate plasticity refers to the capacity of cells sharing the same genome to alter, reverse, or reconfigure their identity under physiological, pathological, or experimental conditions. This property underlies embryonic development, cellular reprogramming, and tissue regeneration, but becomes progressively restricted as lineage identity is stabilized. Embryonic development represents an intrinsic process of fate transitions, whereas reprogramming and regeneration reveal how differentiated cells can dedifferentiate or transdifferentiate under specific conditions. Across these contexts, plasticity is governed by multilayered regulatory networks involving transcription factors, epigenetic regulators, cofactors, and the core transcription machinery. Robust regulatory programs stabilize cell identity, whereas stochastic fluctuations in gene expression and chromatin state can prime cells for fate transitions, adding a tunable dimension to plasticity control. In this review, we synthesize recent advances in the regulation of cell fate plasticity across development, reprogramming, and regeneration, highlighting how transcription factors, epigenetic modifications, transcriptional cofactors, and core transcription machinery cooperate to control cell fate decisions and plasticity.
    DOI:  https://doi.org/10.1016/j.gde.2026.102507
  2. Nat Methods. 2026 Jun 29.
    Spatio-DARLIN enables robust and efficient in situ lineage tracing in mice at single-cell resolution.
    Jianing Gao, Zhanhao Zhang, Daolong Chen, Sijie Diao, Simin Liu, Shou-Wen Wang, Li Li.
      Spatially resolved lineage tracing is essential for understanding how clonal relationships shape tissue architecture. However, such an approach has not been established in mice across different tissues. Here we present Spatio-DARLIN, a versatile method that integrates the high-diversity DARLIN lineage-tracing mouse with sequencing-based spatial transcriptomics. Through a dedicated computational pipeline, Spatio-DARLIN achieves accurate clonal mapping at single-cell resolution and recovers reliable lineage information from ~25-50% of cells in the intestine and brain. Spatio-DARLIN identified stereotyped clonal patterns in the intestinal epithelium and revealed clonal dynamics that were consistent with stem-cell neutral drift. In the brain, we uncovered greater clonal expansion of radial glial cells in the cortex and hippocampus during development than in other regions. Moreover, our data strongly suggested that neuronal progenitors across different nuclei in the hypothalamus were already spatially prepatterned by embryonic day E10. Spatio-DARLIN enables high-resolution study of clonal architecture, expansion and migration across diverse tissues in situ.
    DOI:  https://doi.org/10.1038/s41592-026-03151-5
  3. Cell. 2026 Jun 30. pii: S0092-8674(26)00696-3. [Epub ahead of print]
    Multiscale integration of tissue and chromatin context converts cell heterogeneity into stable intestinal patterning.
    Cornelia Schwayer, Silvia Barbiero, David B Brückner, Koen C Oost, Clara Baader, Nicole A Repina, Jinse Kim, Oscar E Diaz, Isa Uccelli, Laura Capolupo, Ludivine Challet Meylan, Veronique Kalck, Franziska Moos, Simon Suppinger, Qiutan Yang, Jakob Schnabl, Umut Kilik, Matthieu Bourdon, J Gray Camp, Brigitta Stockinger, Alessandra Ferrari, Marc Bühler, Michael B Stadler, Edouard Hannezo, Prisca Liberali.
      Tissue regeneration requires de novo patterning, which has been proposed to be facilitated by cellular heterogeneity. Yet how such heterogeneities are integrated with the mechanochemical state of the tissue and stabilized at the chromatin level into stable, spatially organized fates remains poorly understood. Using in vivo mouse intestinal regeneration models and organoids, we identify a critical density regime that produces a permissive window for heterogeneity in the mechanosensor Yes-associated protein 1 (YAP1). We show that YAP1 heterogeneity is coupled to lineage-biased chromatin accessibility and is decoded through FOXA1, which integrates the permissive chromatin state to Delta-Notch supracellular feedback and lineage commitment. This circuit generates fate bistability and preserves a memory of transient YAP1 activity, thereby maintaining spatial patterning as tissues return to homeostasis after injury. Together, our findings establish a multiscale framework in which tissue-scale mechanics tune single-cell competence and, through FOXA1-mediated bistability, convert transient heterogeneity into stable and self-organized tissue architecture.
    Keywords:  Yap1; epigenetic competence; heterogeneity; image-based phenotyping; intestinal regeneration; mechanics; modeling; multiscale integration; organoids; tissue patterning
    DOI:  https://doi.org/10.1016/j.cell.2026.06.009
  4. Nat Rev Cancer. 2026 Jun 29.
    Imaging the hallmarks of cancer.
    Jan Grimm, Fabian Kiessling, Kevin M Brindle, Douglas Hanahan, Sanjay K Jain, Philippe Lambin, Twan Lammers, King C Li, I Jolanda M de Vries, Wolfgang A Weber, Bettina Weigelin, Bernd J Pichler.
      The hallmarks of cancer were introduced by Hanahan and Weinberg as a conceptual organizing framework to distil the complexity of tumours. This concept of cancer hallmarks has become an enduring theme in cancer research. Moreover, an increasing number of therapeutic strategies are being aimed at targeting these hallmarks. However, translating them into the clinic requires technologies to monitor their effectiveness and biomarkers that can stratify patients for the choice of specific therapies. Tumour heterogeneity and the ability of tumour cells to rapidly mutate and develop evasion strategies makes the development of non-invasive imaging capabilities to interrogate these hallmarks as biomarkers and monitor them longitudinally and quantitatively particularly important. This Review presents a holistic discussion of non-invasive diagnostic imaging capabilities related to the hallmarks of cancer; some hallmarks can be assessed with imaging probes that directly target biomolecules, whereas others can be interrogated indirectly by imaging pathophysiological processes. Additionally, visualizing the hallmarks of cancer can be addressed with artificial intelligence-assisted, multiparametric image analysis (for example, radiomics, radiogenomics and deep learning). The approaches discussed have been evaluated in a translational context, and some of them already have a substantial role in clinical practice, for example, to guide treatment strategies, including surgical resections, radiotherapy and molecularly targeted chemo-, immuno- and radiopharmaceutical therapies.
    DOI:  https://doi.org/10.1038/s41568-026-00950-y
  5. Nature. 2026 Jul 01.
    TROP2 targeting reveals therapy-driven cell state dynamics in colorectal cancer.
    Nuria Vaquero-Siguero, Nikolaos Georgakopoulos, Maria C Puschhof, Ioannis Chiotakakos, Jasmin Meier, Sigrid K Fey, Gabriele Diamante, Manuel Mastel, Aitana Guiseris-Martinez, Guillaume Belthier, Nikolai Schleußner, Julia Volk, Carolin Artmann, Bryce Lim, Ronald Koschny, Cyrill Wehling, Kyanna S Ouyang, Michael Günther, Solveig Kuss, Paula Hoffmeister, Moritz Mall, Jens Neumann, Steffen Ormanns, Martin Schneider, Thomas Schmidt, Jens Puschhof, Andreas Trumpp, Jacco van Rheenen, Julio Saez-Rodriguez, Bruno C Köhler, Rene Jackstadt.
      Metastasis remains the leading cause of cancer-related mortality and is driven by pronounced tumour cell plasticity1. Here we identify the transmembrane glycoprotein trophoblast cell-surface antigen 2 (TROP2) as a marker of poor-prognosis colorectal cancer (CRC) associated with WNTlow, fetal-like tumour cell states that are linked to metastasis and therapy resistance. Functional analyses demonstrate that TROP2+ cells exhibit context-dependent stem-like capacity and the ability to initiate metastatic outgrowth. Given that these detrimental tumour states converge on the cell-surface antigen TROP2, we explored therapeutic targeting of this cell population using clinically relevant TROP2-directed antibody-drug conjugates. Time-resolved analyses reveal therapy-associated dynamics in tumour cell state composition between WNThi LGR5+ states and WNTlowTROP2+ fetal-like states. Conventional chemotherapy promotes the induction of TROP2-expressing cells, whereas TROP2 antibody-drug conjugates selectively target these populations and remodel the tumour cell state landscape. Exploiting this plasticity, combined chemotherapy and TROP2 targeting enhances anti-tumour efficacy in patient-derived models. Together, our findings identify TROP2 as a therapeutic vulnerability of CRC and highlight the importance of targeting tumour cell states to improve therapeutic efficacy and overcome resistance in advanced disease.
    DOI:  https://doi.org/10.1038/s41586-026-10705-2
  6. Nat Genet. 2026 Jun 30.
    Lineage tracing from cellular heritage to disease destiny.
    Huan Zhu, Xiuxiu Liu, Muxue Tang, Kathy O Lui, Bin Zhou.
      The developmental history of a cell fundamentally defines its identity and function. Recent advances in cell lineage tracing now enable high-resolution reconstruction of cellular ancestries in vivo, illuminating how lineage dictates fate in health and disease. This Review highlights recently developed tools, ranging from refined recombinase systems to advanced synthetic and natural barcoding approaches, that facilitate the investigation of pathological lineage programs in cancer, cardiovascular disease and aging. Moving forward, integrating permanent lineage records with single-cell multi-omics promises to provide a unified framework to decode how a cell's past shapes its present state and future potential, heralding a new era for precision medicine.
    DOI:  https://doi.org/10.1038/s41588-026-02628-5
  7. Cancer Discov. 2026 Jul 01. 16(7): 1255-1257
    Spatially Resolved Proteomic Cartography Illuminates the Earliest Molecular Programs in Pancreatic Cancer Evolution.
    Mingyu Yang, Rong Fan.
      Min, Schweizer, and colleagues use artificial intelligence-powered deep visual proteomics to generate a spatial proteomic atlas of pancreatic cancer precursor evolution, revealing that major metabolic and inflammatory reprogramming occurs long before overt histologic transformation. More broadly, the study highlights the emerging potential of spatial proteomics and multiomics to bridge histopathology with molecular pathology and precision oncology. See related article by Min et al., p. 1323.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1022
  8. Curr Opin Cell Biol. 2026 Jun 27. pii: S0955-0674(26)00059-1. [Epub ahead of print]101 102671
    Patterns in motion: Choreographing dynamic cell behaviours during tissue repair.
    Helen Weavers.
      Tissue repair is a dynamic, multicellular response that relies on the precise spatiotemporal coordination of diverse cell types. Here, we discuss how recent advances have accelerated our mechanistic understanding of these collective cellular behaviours, particularly in epithelial barrier tissues like the skin. We highlight studies unravelling the intricate crosstalk that patterns cell behaviours across the repairing tissue and how vulnerable cells are endowed with striking stress resilience and memory. The integration of cutting-edge live imaging, single-cell profiling and computational approaches are now revealing the complexities of effective and pathological repair at an unprecedented resolution, opening new avenues for therapeutic intervention.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102671
  9. Science. 2026 Jul 02. 393(6806): 49
    Ecology of the gut microbiome.
    Erik Bakkeren.
      Microbial competition can be harnessed to prevent and cure deadly diseases.
    DOI:  https://doi.org/10.1126/science.aej2365
  10. Nat Genet. 2026 Jul 02.
    Mutational scanning reveals substrate-assisted autoregulation of the WNT destruction complex.
    Murugesh Padmanarayana, Saira Sakalas, Parijat Sarkar, Mengxiao Ma, Ethan R Garvin, Ethan Lee, Steven M Corsello, Sebastian Guettler, Ganesh V Pusapati, Rajat Rohatgi.
      The β-catenin destruction complex (BDC) regulates WNT-β-catenin signaling and is a prime therapeutic target in colorectal cancer, yet its biochemical complexity has hindered mechanistic understanding. We mapped the sequence-function landscape of the BDC using tiled base editor screens across its components CTNNB1, AXIN1, APC and GSK3B. Amongst ~150 previously unreported mutations that affected WNT signaling, we discovered gain-of-function and separation-of-function alleles that reveal mechanisms of complex assembly, including a β-catenin region regulating TCF/LEF transcription factor binding. Critically, we found that the AXIN1-β-catenin interface controls signaling flux through the oncogenic BDC found in APC-mutant cancers. In cells expressing truncated APC, β-catenin itself scaffolds BDC assembly, establishing a substrate-assisted autoregulatory mechanism. This architecture represents an unexploited therapeutic vulnerability: strengthening the AXIN1-β-catenin interaction restores destruction complex function and impairs the growth of colorectal cancer cells. Our mutational resource provides a foundation for mechanistic understanding and therapeutic targeting of the WNT pathway.
    DOI:  https://doi.org/10.1038/s41588-026-02662-3
  11. Nat Biotechnol. 2026 Jul 01.
    A genome-scale CRISPRi perturbation atlas of human induced pluripotent stem cells.
    Sami Nourreddine, Yesh Doctor, Amir Dailamy, Yi-Hung Lee, Jan N Hansen, Rebecca Chinn, Antoine Forget, Benjamin Polacco, Monita Muralidharan, Alina Sigaeva, Sushant Sunder, Emily Pan, Jiahao Gao, Jake Y Chen, Timothy Clark, Jillian Parker, Kirsten Obernier, Christian Metallo, Trey Ideker, Emma Lundberg, Nevan Krogan, Prashant Mali.
      Comprehensively mapping the relationship between genotype and phenotype offers essential insights into how a cell's state arises from its genetic components. Toward this goal, we generated an expressed genome-scale CRISPRi perturbation cell atlas in KOLF2.1J human induced pluripotent stem cells, mapping transcriptional phenotypes associated with 11,692 perturbed genes across >2.5 million single cells. Using correlations among perturbed phenotypes, we created a cell map of the pluripotent state, demonstrating rich recapitulation of functionally related protein complexes. We then explored the atlas to uncover metabolic factor ZBTB41 and pluripotency regulator RNF7, validating their functions through metabolic tracing, immunofluorescence and protein-protein interaction assays. Lastly, we leveraged the atlas to generate a genome-scale screen of A-to-I RNA-editing modulators assayed through direct transcriptome-wide RNA editing, uncovering and mechanistically validating DBR1 as a potent regulator. Taken together, our data provide a comprehensive resource for interrogating the regulatory networks governing pluripotency, which is accessible at https://y-doctor.github.io/KOLF2.1J_Perturbation_Cell_Atlas/ .
    DOI:  https://doi.org/10.1038/s41587-026-03199-w
  12. Nature. 2026 Jun 29.
    Daily briefing: Editing the epigenome with CRISPR to treat disease.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-026-02075-6
  13. Nat Rev Immunol. 2026 Jul 02.
    A guide to CAR T cell therapies: development, current status and future prospects.
    Hind Rafei, Ranjan Upadhyay, Padmanee Sharma.
      Since the first clinical approval in 2017, chimeric antigen receptor (CAR) T cell therapy has emerged as one of the most powerful modalities for redirecting the immune response against cancer. Building on decades of foundational discoveries in T cell biology and synthetic immunoengineering, CAR T cell therapy has transformed the treatment of B cell malignancies, resulting in durable remissions in patients with B cell leukaemias, lymphomas and multiple myeloma. Next-generation CAR designs are now expanding the reach of this approach into autoimmune disease and solid tumours. Innovations in gene editing, allogeneic manufacturing and in vivo delivery are improving the scalability, safety and accessibility of CAR T cell therapies, although challenges persist in overcoming antigen heterogeneity and tumour microenvironmental barriers and in promoting the long-term persistence of CAR T cells. In this Review, we summarize the key discoveries that laid the foundations for CAR T cell therapies and provide a broad overview of the current principles of CAR design, their clinical development and emerging strategies aimed at enhancing efficacy, broadening indications and achieving durable immune control across disease types.
    DOI:  https://doi.org/10.1038/s41577-026-01322-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒27 at 15:20.