bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–05–24
twenty-two papers selected by
Xiao Qin, University of Oxford
  1. Mesenchymal stromal/stem cells in tumour initiation, progression and therapy.
  2. Computational approaches for multimodal lineage tracing.
  3. Parallel Activation and Interference CRISPR (PAIR) with Sequencing Uncovers DNA Repair Networks Guiding Precision Cell Engineering.
  4. Human pancreatic progenitor organoids define genetic and epigenetic barriers to early PDAC transformation.
  5. Genome-wide chromatin recording resolves dynamic cell state changes.
  6. PEPR-GNN: Perturbation-Enhancer-Promoter-RNA Graph Neural Networks for Multiome Perturb-Seq modeling of regulomes.
  7. Mechanisms coordinating exit from the stem cell state in mammals.
  8. Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer.
  9. Robust identification of cell-cell communication heterogeneity in single cells.
  10. Asynchronous evolution of epithelium and stroma differentiates precursor lesions from pancreatic cancer.
  11. Pioneer: Dynamical Systems Biology for Spatiotemporal Omics Data.
  12. Comprehensive Lineage Tracing Maps the Landscape of Cell Fate Decisions in Mouse Embryogenesis.
  13. The Hippo Pathway in Intestinal Regeneration, Fetal Reprogramming, and Tumorigenesis.
  14. How is agentic AI changing how we do science?
  15. Integrating multi-omics data for next-generation cancer research and precision medicine.
  16. ETS1 Orchestrates a Hybrid EMT Program Driving Metastasis and Immune Evasion.
  17. Temporal variations of the gut microbiome in human health.
  18. AI-enabled multi-omics integration in colorectal cancer: from molecular stratification to clinical translation.
  19. Regulation of immune checkpoint molecules in cancer immune evasion and therapy.
  20. The discovery of gene imprinting.
  21. Selective Elimination of TP53 Mutant Cells by Transcript-Activated Chromatin Shredding.
  22. Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease.
  1. Nat Rev Cancer. 2026 May 20.
    Mesenchymal stromal/stem cells in tumour initiation, progression and therapy.
    Geyon L Garcia, Roja Baruwal, Swathi Suresh, Ananya Kapur Britt, Angelina Li, Huda I Atiya, Lan Coffman.
      The expanding study of mesenchymal stromal/stem cells (MSC) in cancer has amounted to a growing understanding of their underlying biology in malignant and non-malignant settings. In addition to supporting homeostasis in nearly all normal tissues, MSCs also serve as stromal support for a diverse set of malignancies, the most studied being ovarian, breast, brain, blood and colorectal cancers. Their ability to localize to and shape the stromal microenvironment of solid tumours or haematologic malignancies results in increased tumour cell growth, metastasis and survival and promotes the enrichment of the cancer stem cell population, all of which contribute to poor patient outcomes. Here we summarize the known roles MSCs have in promoting or inhibiting carcinogenesis. We highlight emerging concepts including epigenetic reprogramming of MSCs to switch from a tumour-suppressive to tumour-supportive phenotype, their role in cancer initiation, and novel mechanisms of immune modulation. We also cover advances in the development of MSC-targeted treatment modalities for cancer therapy. In addition, given their inherent adaptability, we discuss how MSCs are being co-opted as tools for drug delivery and discuss ongoing challenges in MSC-based therapies.
    DOI:  https://doi.org/10.1038/s41568-026-00936-w
  2. Nat Rev Genet. 2026 May 18.
    Computational approaches for multimodal lineage tracing.
    Kun Wang, Xionglei He, Zheng Hu.
      Understanding how cells commit to distinct fates over time is fundamental to elucidating the principles and mechanisms that govern organismal development, tissue regeneration and disease progression. Multimodal lineage tracing, which couples heritable lineage information with single-cell multi-omics, has revolutionized our ability to chart cellular dynamics and fate decisions at unprecedented resolution. However, the resulting datasets are inherently complex and heterogeneous, calling for sophisticated computational frameworks capable of transforming raw measurements into coherent biological insights. Here we comprehensively survey recent methodological advances that substantially expand the computational toolkit for analysing lineage-resolved, single-cell multi-omic data, enabling more accurate lineage reconstruction, trajectory inference, ancestral state estimation and identification of molecular programmes driving cell-state transitions. Emerging high-resolution lineage-tracing technologies and deep learning-based analytical models promise to further unlock the full potential of multimodal lineage tracing, offering an increasingly complete and quantitative view of cellular evolution in both health and disease.
    DOI:  https://doi.org/10.1038/s41576-026-00969-9
  3. bioRxiv. 2026 May 08. pii: 2026.05.08.722799. [Epub ahead of print]
    Parallel Activation and Interference CRISPR (PAIR) with Sequencing Uncovers DNA Repair Networks Guiding Precision Cell Engineering.
    Chen Chang, Dailin Gan, Lu Diao, Lei Wang, Chantale Lacelle, Gary C Hon, Jun Li, Min Zhao, Siyuan Zhang.
      The dynamic balance of cellular homeostasis is often maintained by opposing regulatory pathways, yet most genetic screens interrogate them in one direction and therefore miss the bidirectional gene-gene interactions that shape complex phenotypes such as DNA damage response (DDR). Here, we present PAIR (Parallel Activation and Interference CRISPR), a bidirectional perturbation platform that enables simultaneous activation and suppression of distinct genes within the same cell using CRISPR activation (CRISPRa) and Cas13d RNA knockdown. Applying PAIR to the CRISPR/Cas9 induced DSB repair screen, we mapped gene-gene interactions across competing repair branches and identify synergistic perturbations, including NBN activation combined with suppression of end-joining factors, that shift repair outcomes toward homology-directed repair (HDR) and improve the precision of CRISPR-based gene editing. Using coupled PAIR with single-cell transcriptomic, we further demonstrated that NBN activation induces inflammatory and interferon programs, whereas co-suppression of end-joining factors buffers this response, revealing transcriptional states missed by conventional unidirectional perturbations. To translate these findings into non-viral chimeric antigen receptor (CAR) T cell engineering, we developed an mRNA-based strategy for parallel overexpression and knockdown of NBN-anchored DDR effectors in primary T cells, priming the T cells into a transient HDR-favored state that enhances the efficiency of CAR knock-in on the TRAC locus. Together, the PAIR system provides a general framework for studying opposing regulatory networks, uncovering hidden cell states, and guiding cell-state engineering through bidirectional perturbation.
    DOI:  https://doi.org/10.64898/2026.05.08.722799
  4. Dev Cell. 2026 May 19. pii: S1534-5807(26)00159-0. [Epub ahead of print]
    Human pancreatic progenitor organoids define genetic and epigenetic barriers to early PDAC transformation.
    Xian Zhang, Wilfred Wong, Hyein S Cho, Dapeng Yang, Gary Dixon, Renhe Luo, Dingyu Liu, Denis Torre, Shigeaki Umeda, Federico González, Gokce Askan, Aslihan Yavas, Jeyaram Ravichandran Damodaran, Robert W Rickert, Rajya Kappagantula, Fong Cheng Pan, Victoria G Aveson, Adrien Grimont, William B Fall, Xianming Wang, Julian Pulecio, Samuel J Kaplan, Heng Pan, Xianlu Laura Peng, Jen Jen Yeh, Steven D Leach, Christine A Iacobuzio-Donahue, Rohit Chandwani, Christina S Leslie, Danwei Huangfu.
      The lack of accurate human models that recapitulate pancreatic ductal adenocarcinoma (PDAC) initiation has hindered therapeutic development. Using pluripotent stem cell-derived pancreatic progenitor organoids, we established a human PDAC model that faithfully reproduces the genetic, epigenetic, and transcriptomic trajectories of tumor initiation and progression, validated against clinical datasets and tumor histopathology. We demonstrate that CDKN2A loss, which is nearly universal in patients but dispensable in mouse models, is essential for neoplastic transformation when combined with KRAS and TP53 mutations, whereas SMAD4 loss promotes tumor progression. Multi-omics profiling reveals epigenetic repression of the pancreatic lineage program during PDAC initiation, alongside AP-1-driven chromatin remodeling. We identify TET1 suppression as a mechanistic link between oncogenic ERK signaling and hypermethylation of essential pancreatic transcription factors. This model captures genetic and epigenetic determinants of human PDAC, reveals antagonism between oncogenic and lineage restriction programs, and supports TET-based lineage restoration as a potential early intervention strategy.
    Keywords:  DNA methylation; TET1 suppression; activator protein-1; chromatin remodeling; gene editing; lineage plasticity; oncogenic KRAS; pancreatic ductal adenocarcinoma; pancreatic progenitor organoid; tumor suppressor gene
    DOI:  https://doi.org/10.1016/j.devcel.2026.04.012
  5. bioRxiv. 2026 May 04. pii: 2025.08.05.668773. [Epub ahead of print]
    Genome-wide chromatin recording resolves dynamic cell state changes.
    Yodai Takei, Jordan A Lay, James M Linton, Duncan M Chadly, Yoshiki Ochiai, Ron Hadas, Andrew A Perez, Mario R Blanco, Paola Laurino, Mitchell Guttman, Michael B Elowitz.
      Understanding how the chromatin state of a cell influences its future behavior is a major challenge throughout biology. However, most chromatin profiling methods are limited to endpoint assays. Here, we present LagTag, a method for recovery of earlier and endpoint chromatin states in the same mammalian cells. In this approach, transient expression of bacterial adenine methyltransferase fusions records the DNA binding profiles of chromatin-associated proteins of interest at earlier timepoints. Subsequent tagmentation and sequencing recovers the earlier chromatin profile from adenine methylation profiles, alongside endpoint profiles of endogenous chromatin-associated proteins. We verified that LagTag profiles aligned with those from established methods in mouse and human cells. More importantly, LagTag was able to record and recover dynamic chromatin state transitions during mouse embryonic stem cell differentiation, capturing transcriptional signatures from pre- and post-differentiation timepoints within the same cell population. LagTag thus provides a foundation for temporally resolved chromatin profiling.
    DOI:  https://doi.org/10.1101/2025.08.05.668773
  6. bioRxiv. 2026 May 06. pii: 2026.05.05.722311. [Epub ahead of print]
    PEPR-GNN: Perturbation-Enhancer-Promoter-RNA Graph Neural Networks for Multiome Perturb-Seq modeling of regulomes.
    Zachary Markham, Boxun Li, Landon Nguyen, Lei Wang, Nikhil V Munshi, Gary C Hon.
      Cellular reprogramming is a complex interplay between perturbations and regulatory elements, culminating in gene expression changes. Current computational approaches do not explicitly model these regulatory interactions. Here, we performed combinatorial reprogramming with cardiac transcription factors, followed by Multiome Perturb-Seq to measure perturbations, open chromatin, and gene expression in individual cells. We then developed PEPR-GNN (Perturbation-Enhancer-Promoter-RNA Graph Neural Network), a theoretical and computational framework to model regulome responses during complex genetic perturbations. By statistically associating gene regulatory relationships, PEPR-GNN organizes genes into regulomes with shared gene regulatory responses to reprogramming, including easy-to-reprogram cardiac genes, difficult-to-reprogram fibroblast genes, and context-specific genes where the impact of a reprogramming factor depends on the presence of others. Finally, we use PEPR-GNN for in silico modeling of how genetic modifications of enhancers can be used to tune gene responses to reprogramming. Overall, through the use of causal perturbation information and an enhancer-aware regulome model of gene regulation, PEPR-GNN can effectively model complex cellular responses to perturbation.
    Highlights: Multiome Perturb-Seq of GHMT reprogramming in MEFs with RNA/ATAC-Seq readout.PEPR-GNN: a computational framework to model perturbation-induced regulomes.PEPR-GNN aids the interpretation of regulomes by diverse reprogramming responses.PEPR-GNN enables in silico perturbation to tune gene responses to reprogramming.
    DOI:  https://doi.org/10.64898/2026.05.05.722311
  7. Genes Dev. 2026 May 19.
    Mechanisms coordinating exit from the stem cell state in mammals.
    Emily J Park, Florencia Levin-Ferreyra, Bruno Di Stefano.
      Differentiation requires coordinated exit from the stem cell state, during which gene regulatory networks sustaining self-renewal are dismantled, while lineage-specific programs are activated. This transition is governed by chromatin modifications, transcriptional networks, RNA processing, translational control, and metabolic rewiring that must operate with temporal precision. Despite significant progress in identifying individual regulatory components, understanding how these layers integrate to orchestrate irreversible cell fate commitment remains a fundamental challenge. This review examines common and unique regulatory principles governing stem cell exit, from totipotency during early embryogenesis to tissue-specific stem cell differentiation in adults. We synthesize recent findings on regulatory mechanisms across mammalian species, highlight species-specific adaptations, and explore the concept of reversibility in differentiation. Elucidating these principles has broad implications for regenerative medicine, cellular reprogramming, and diseases in which differentiation programs are corrupted.
    Keywords:  RNA processing; cell fate; chromatin; epigenetics; pluripotency; stem cells
    DOI:  https://doi.org/10.1101/gad.353584.125
  8. Cancer Cell. 2026 May 21. pii: S1535-6108(26)00220-5. [Epub ahead of print]
    Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer.
    Salvador Alonso, Kevan Chu, Elizabeth Granowsky, Valeria Saraiba Rabanales, Marie J Parsons, Himari Gunasinghe, Jinru Shia, Rona Yaeger, Lukas E Dow.
      KRAS is mutationally activated in 45%-50% of colorectal cancer (CRC) cases, and while KRAS-targeted therapies have shown clinical promise, drug resistance limits their efficacy. To explore the mechanisms underlying KRAS inhibitor resistance, we use targeted exome sequencing and spatial transcriptomics on patient-matched CRC biopsies following combined treatment with KRASG12C and EGFR inhibitors. We show that acquired genetic events are identified in most patients at progression but are often subclonal and coexist with transcriptional adaptive states. Mesenchymal, YAP, and fetal-like transcriptional signatures predominate in resistant tumors, while inflammatory programs are induced early on treatment. Single-cell spatial analysis reveals intratumoral heterogeneity, with diverse adaptive states in different zones of individual tumors. Using human and murine organoid models, we show that drug-induced inflammatory programs are, at least in part, cancer-cell autonomous, and precede the emergence of drug resistance. We identify TBK1 as a target to abrogate the inflammatory adaptive phase and enhance responses to KRAS inhibition.
    Keywords:  CRC; KRAS; TBK1; inflammation; plasticity
    DOI:  https://doi.org/10.1016/j.ccell.2026.04.009
  9. bioRxiv. 2026 May 04. pii: 2026.04.29.721691. [Epub ahead of print]
    Robust identification of cell-cell communication heterogeneity in single cells.
    Federico Bocci, Yunlong Jia, Scott Atwood, Qing Nie.
      Communication between cells modulates cell fate decisions by relaying information across tissues and inducing intracellular responses mediated by gene regulatory networks. Inference of cell-cell communication from high throughput data such as single cell transcriptomics is gaining popularity due to the high data availability and ease to automate modeling over hundreds of signaling pathways. Studying how cell-cell communication operates across biological scales and influences cell fate decisions, however, remain a major open question. Here, we present scRICH, a framework and package that integrates mechanism-based, multiscale mathematical modeling with learning strategies to capture the complexity of cell-cell communication from single-cell and spatial transcriptomics data. scRICH unravels the heterogeneity of communication behavior within cell types, links cell-cell communication to cell fate decisions by incorporating dynamical information of RNA splicing, and connects the scales of cell-cell interactions and intracellular response by constructing multilayer regulatory networks. We validate scRICH with new experiments on EGF ligand/receptor co-expression in keratinocytes from skin-equivalent organoid, and compare these computational predictions against existing CCC inference methods. Applying scRICH to multiple biological scenarios demonstrate its ability to capture emerging relations between distinct cell-cell communication pathways, interactions at the onset of cell fate decision, and emerging trends in cell-cell communications along cell lineages and in space.
    DOI:  https://doi.org/10.64898/2026.04.29.721691
  10. Cancer Discov. 2026 May 21.
    Asynchronous evolution of epithelium and stroma differentiates precursor lesions from pancreatic cancer.
    Ahmed M Elhossiny, Padma Kadiyala, Jude Ogechukwu Okoye, Harrison L Hiraki, Megan C Procario, Thejaswini Giridharan, Hannah R Watkoske, Mariana Tannus Ruckert, Jiayue Wang, Brian D Griffith, Alexander W Bray, Jamie N Mills, Carlos E Espinoza, Jörg Zeller, Nicole Peterson, Filip Bednar, Yaqing Zhang, Arvind Rao, Costas A Lyssiotis, Julianne M Szczepanski, Jiaqi Shi, Atul Deshpande, Anirban Maitra, Elana J Fertig, Eileen S Carpenter, Timothy L Frankel, Marina Pasca di Magliano.
      Pancreatic intraepithelial neoplasia (PanIN) precedes pancreatic cancer, a deadly disease characterized by an extensive tumor microenvironment. How the microenvironment evolves during cancer progression is largely unknown, as PanINs are microscopic and non-diseased pancreas samples are exceedingly rare, while adjacent normal samples are disrupted by the presence of malignancy. Leveraging donor organs and spatial technologies we mapped the evolution of PanIN to cancer. The PanIN epithelial component falls on a continuum with cancer while the PanIN microenvironment is drastically distinct. Progression to cancer is accompanied by profound geographical reorganization of myeloid cells and lymphocytes and the formation of a cancer-specific fibroblast population characterized by high levels of Smooth Muscle Actin, LRRC15 and the WNT signaling component LEF1. Together, our data show asynchronous evolution of epithelial and stromal components during pancreatic carcinogenesis. Lack of stromal reprogramming might explain why most PanINs do not progress to cancer. Compiled data available at https://pascadimagliano-lab.github.io/PancAtlas.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2001
  11. J Mol Biol. 2026 May 18. pii: S0022-2836(26)00237-8. [Epub ahead of print] 169864
    Pioneer: Dynamical Systems Biology for Spatiotemporal Omics Data.
    Luonan Chen.
      Dynamical systems biology is an emerging interdisciplinary framework that aims to understand how complex biological processes arise from time-dependent interactions among molecular, cellular, and tissue-level components. The rapid development of high-throughput technologies, including single-cell and spatial multi-omics, has generated rich spatiotemporal datasets that demand theoretical and computational tools beyond static analyses. In this review, we highlight recent advances that connect dynamical systems theory with modern omics measurements, focusing on three complementary directions. First, we summarize dynamical network biomarkers theory for detecting tipping points and early-warning signals of critical transitions during disease progression and cell-fate decisions. Second, we discuss energy-landscape approaches that provide quantitative descriptions of stability, transition barriers, and state switching in noisy biological systems. Third, we review cellular dynamical models for reconstructing continuous trajectories and inferring transition dynamics from single-cell omics data. Together, these perspectives provide a unified dynamical view of living systems and support the development of dynamical virtual cells and dynamical foundation models.
    Keywords:  dynamical network biomarker; dynamical optimal transport; dynamical systems biology; energy landscape theory; single-cell omics
    DOI:  https://doi.org/10.1016/j.jmb.2026.169864
  12. bioRxiv. 2026 May 09. pii: 2026.05.07.722278. [Epub ahead of print]
    Comprehensive Lineage Tracing Maps the Landscape of Cell Fate Decisions in Mouse Embryogenesis.
    William N Colgan, Luke W Koblan, JoAnne Villagrana, Tien-Chi Jason Hou, Minming Wang, Gokul Gowri, Whitney Chandler, Leonardo A Sepúlveda, Didar Ciftci, Karina Smolyar, Alicia Young, Lars Wittler, Styliani Markoulaki, Kyle Loh, Xiaowei Zhuang, Nir Yosef, Zachary D Smith, Jonathan S Weissman.
      A comprehensive cell fate map of mammalian embryogenesis has remained out of reach due to the scale, cellular diversity, and non-deterministic nature of development in utero . Here, we use PEtracer to continuously install heritable genetic marks as cells divide, reconstructing lineage trees that resolve ∼75% of cell divisions across >1.5 million cells from 16 mouse embryos collected at half-day intervals from E7.5-E10.0. We pair these trees with deep transcriptional profiling to chart the landscape of cell fate decisions during gastrulation and early organogenesis. Using these data, we quantify cell fate biases, restriction timing, progenitor pool sizes, and lineage relationships across the embryo, revealing strikingly reproducible lineage architecture across replicate embryos despite the regulative flexibility of mammalian development. We further show how lineage, spatial position, and signaling jointly determine fate outcomes and timing, with their relative influence varying by tissue. This dataset provides a quantitative framework for understanding cell fate specification and a lineage-resolved reference for generating and contextualizing developmental hypotheses at organismal scale.
    DOI:  https://doi.org/10.64898/2026.05.07.722278
  13. Cold Spring Harb Perspect Biol. 2026 May 18. pii: a041915. [Epub ahead of print]
    The Hippo Pathway in Intestinal Regeneration, Fetal Reprogramming, and Tumorigenesis.
    Vanessa Man, Jeffrey L Wrana.
      The Hippo signaling pathway, first identified in Drosophila, is a conserved regulator of organ size and tissue homeostasis that balances proliferation and apoptosis. In mammals, its core kinases mammalian Sterile 20-like kinases 1 and 2 (MST1/2) and large tumor suppressor kinases 1 and 2 (LATS1/2) restrict the transcriptional coactivators Yes-associated protein 1 (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), whose nuclear translocation drives cell proliferation and survival. In the intestine, YAP/TAZ activity is normally repressed to maintain homeostasis, but transient activation following injury promotes regeneration. Injury-induced YAP signaling triggers a regenerative transcriptional program marked by fetal gene re-expression and the emergence of Clusterin (Clu)-positive revival stem cells (revSCs), which restore leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) intestinal stem cells and epithelial integrity. Cross talk between Hippo, Wingless-related integration site (WNT), transforming growth factor β (TGF-β), and p53 signaling orchestrates this dynamic repair process, with precise temporal control of YAP essential for successful regeneration. Dysregulation of these interactions contributes to colorectal cancer tumorigenesis, highlighting the Hippo pathway as a central hub linking intestinal homeostasis, regeneration, and cancer.
    DOI:  https://doi.org/10.1101/cshperspect.a041915
  14. Cell Syst. 2026 May 20. pii: S2405-4712(26)00099-2. [Epub ahead of print]17(5): 101617
    How is agentic AI changing how we do science?
    James Zou, L Stirling Churchman, Bo Xia, Dmitrijs Lvovs, Elana J Fertig, Jianyang Zeng, Yogesh Goyal, Jian Ma.
      
    DOI:  https://doi.org/10.1016/j.cels.2026.101617
  15. Clin Transl Oncol. 2026 May 20.
    Integrating multi-omics data for next-generation cancer research and precision medicine.
    CAPCI
      Multi-omics is the coordinated acquisition, integration, and interpretation of multiple datasets generated from diverse molecular layers of a biological system, intending to capture a comprehensive understanding of interactions between molecular hierarchies and reveal the complex regulatory architecture underlying cellular states, physiological processes, and disease phenotypes. Multi-omics integration signifies a transformative approach in cancer research, facilitating a systems-level comprehension of tumor biology that goes beyond the analysis of individual data layers. Through the combined analysis of data from genomics, transcriptomics, epigenomics, proteomics, and metabolomics, this method reveals the intricate molecular networks that influence tumorigenesis and its variability. High-throughput technologies play a crucial role in this context, enabling the identification of new biomarkers, the detection of actionable therapeutic targets, and the classification of unique cancer subtypes. Integrative omics is essentially transforming precision oncology by enhancing patient risk assessment and forecasting treatment responses, thus guiding personalized diagnosis and therapy approaches. The effectiveness of this method increases when molecular data are integrated with clinical and imaging information, resulting in stronger predictive models for personalized patient treatment. Nonetheless, considerable obstacles remain, such as the integration of diverse data, the adjustment of batch effects, and the clinical understandability of intricate computational models. Tackling these challenges requires sophisticated machine learning methods, uniform data processing workflows, and ongoing cross-disciplinary teamwork. With the advancement of these methodologies, multi-omics integration will act as the essential link between large-scale data and precision medicine, providing unmatched chances to unravel the intricacies of cancer and produce effective, tailored treatments. This review highlights the latest advancements, ongoing challenges, and future pathways that are influencing the next wave of cancer research and clinical applications.
    Keywords:  Artificial intelligence; Biomarker discovery; Cancer stem cell; Cancer vaccine; Immune cell cross-talk; Machine learning; Multi-omics integration; Neoantigen; Precision medicine; Single-cell omics; Spatial transcriptomics; Systems biology; Therapeutic stratification; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12094-026-04368-8
  16. Cancer Res. 2026 May 19.
    ETS1 Orchestrates a Hybrid EMT Program Driving Metastasis and Immune Evasion.
    Benjamin Ziman, Talia A Wenger, Chehyun Nam, Qian Yang, Daniel Arnaudov, Thomas Tilton, Megha Sheth, Zhixuan Jing, Yuhao Pan, Joseph A Vargas, Yong Teng, Uttam K Sinha, Young Min Park, De-Chen Lin.
      Transcriptional intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers. Investigation into the ITH programs that drive tumor metastasis and immune evasion could help identify potential treatment and prevention approaches. Through single-cell RNA sequencing analysis of upper aerodigestive squamous cell carcinoma (UASCC) cells and patient tumors, we uncovered a hybrid epithelial-mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating the STAT1 and CD274 (PD-L1) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, high ETS1 expression in tumors strongly correlated with poor survival and resistance to immune checkpoint blockade (ICB) across multiple cohorts. Drug screening demonstrated that ETS1-high cancers were vulnerable to HSP90 inhibitors (e.g., alvespimycin), which suppress ETS1 by disrupting HIF1α-mediated transcriptional activation. Together, this work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3134
  17. Lancet Microbe. 2027 Feb 10. pii: S2666-5247(26)00043-1. [Epub ahead of print] 101388
    Temporal variations of the gut microbiome in human health.
    Shuqin Zeng, Alexandre Almeida, Dezhi Mu, Shaopu Wang.
      The colonisation of the human gut microbiome commences at birth and continues to evolve throughout the lifespan. A balanced symbiotic relationship between the host and gut microbiome is essential for maintaining overall health. This two-part Series presents a comprehensive overview of the gut microbiome across temporal and spatial dimensions, considering diurnal, seasonal, and lifespan variations while covering the entire gastrointestinal tract. We also discuss the extrinsic and intrinsic factors that shape the microbial ecosystem and affect host homoeostasis, health, and disease susceptibility. In this first Series paper, we summarise current knowledge on the microbial succession and evolutionary trajectory of the gut microbiome from neonates to adults aged 100 years and older, subsequently focusing on diurnal rhythms and seasonal patterns. We then discuss how these temporal variations in the gut microbiome are determined and how they contribute to beneficial or detrimental health outcomes in the host. Overall, elucidating the multiscale temporal dynamics of the human gut microbiome will open crucial opportunities to expand knowledge of host-microbiome interactions and their biological and clinical implications.
    DOI:  https://doi.org/10.1016/j.lanmic.2026.101388
  18. Front Cell Dev Biol. 2026 ;14 1797221
    AI-enabled multi-omics integration in colorectal cancer: from molecular stratification to clinical translation.
    Honghua Su, Tiangui Wang, Chaofan Chen.
      Colorectal cancer (CRC) remains a heterogeneous disease for which improved molecular stratification is needed across the clinical pathway. Multi-omics technologies have expanded insight into CRC biology, and artificial intelligence (AI) has created new possibilities for integrating molecular, pathological, imaging, and clinical data. This review examines how these approaches are being applied across screening, diagnosis, treatment, and prognosis, with particular emphasis on their clinical relevance and translational limitations. We argue that, despite encouraging advances in biomarker discovery and risk prediction, most current studies remain retrospective and are constrained by heterogeneity of data sources, limited standardisation, weak interpretability, and insufficient external or prospective validation. AI-enabled multi-omics integration has substantial potential in CRC, but meaningful clinical impact will require rigorous validation and implementation frameworks suited to routine care.
    Keywords:  artificial intelligence; biomarker discovery; clinical decision support; colorectal cancer; machine learning; multi-omics; precision medicine
    DOI:  https://doi.org/10.3389/fcell.2026.1797221
  19. Nat Rev Cancer. 2026 May 18.
    Regulation of immune checkpoint molecules in cancer immune evasion and therapy.
    Cansu Eris, Cheng Zu, Yanling Xiao, Michael Platten, Chong Sun.
      Immune checkpoint molecules are essential regulators of immune homeostasis, maintaining the balance between activation and tolerance. In cancer, tumours exploit checkpoint pathways to suppress antitumour immunity and promote progression. The advent of immune checkpoint inhibitors, particularly those that target the clinically validated PDL1-PD1 and CTLA4 axes, has transformed cancer therapy, and the LAG3 axis has recently entered clinical practice, yet most patients experience limited or transient benefit, often because the checkpoint molecules become dysregulated. Here, we examine how multilayered regulatory mechanisms operating at the genetic, epigenetic, transcriptional, post-transcriptional, translational and post-translational levels collectively shape checkpoint abundance and function in tumour and immune cells. We further connect these regulatory processes to immune evasion and therapeutic resistance and highlight how this knowledge informs biomarker development and mechanism-guided strategies to improve immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41568-026-00934-y
  20. Nat Rev Genet. 2026 May 19.
    The discovery of gene imprinting.
    Mary Gehring.
      
    DOI:  https://doi.org/10.1038/s41576-026-00973-z
  21. bioRxiv. 2026 May 09. pii: 2026.05.08.723607. [Epub ahead of print]
    Selective Elimination of TP53 Mutant Cells by Transcript-Activated Chromatin Shredding.
    Jingkun Zeng, Zhiyuan Cheng, Huadong Chen, Jared Thompson, Kadin T Crosby, Hesong Han, Wayne Ngo, Chenglong Xia, Daniel Rosas-Rivera, Min Hyung Kang, Ying Mao, Giselle Lee, John F X Diffley, Yixuan Song, Longhui Qiu, Nathan M Krah, Niren Murthy, Ryan N Jackson, Yang Liu, Alan Ashworth, Jennifer A Doudna.
      Genetic mutations that drive cancer often occur in tumor suppressor proteins, including the p53 transcription factor which is altered in ∼40-50% of cases 1,2 . However, current therapies fail to target most such mutations because the mutant proteins typically lack defined drug-binding pockets, and restoring the endogenous function has proven challenging. Here, we programmed CRISPR-Cas12a2, an RNA-guided nuclease with trans -nucleolytic cleavage activities 3,4 , to selectively kill cancer cells by targeting cancer-specific transcripts. This approach eliminates cells by inducing trans chromatin cleavage, triggering DNA damage and cell death. Unlike existing methods, RNA-guided Cas12a2 senses cellular RNA signatures to shred chromatin, enabling precise targeting of undruggable mutations. Transcript-activated chromatin shredding provides an innovative paradigm to develop precision disease treatments for undruggable targets.
    DOI:  https://doi.org/10.64898/2026.05.08.723607
  22. bioRxiv. 2026 May 06. pii: 2026.05.01.720931. [Epub ahead of print]
    Stromal state plasticity defines risk and therapeutic opportunity in recalcitrant inflammatory bowel disease.
    Courtney Tindle, Harrison M Penrose, Saptarshi Sinha, Madhubanti Mullick, Kennith Carpio-Perkins, Mason Hayashi, Sophia S Carpinelli, Ella McLaren, Chia-Chian Hsieh, Kameron Zablan, Helen N Le, Jennifer Neill, Gajanan D Katkar, William J Sandborn, Brigid S Boland, Pradipta Ghosh.
      Inflammatory bowel diseases (IBD) remain a relapsing, treatment-refractory disorder marked by progressive tissue injury and inflammation despite expanding immune-targeted therapies. We established a prospective cohort integrating stromal biobanking, functional phenotyping, cross-cohort benchmarking, and outcome modeling to define disease-anchored cellular states. Colonic myofibroblasts from 34 individuals spanning health, ulcerative colitis, and Crohn's disease resolved into two dominant states : inflammatory ( IMFs ) and quiescent ( QMFs ) myofibroblasts. IMF predominance at recruitment forecasted progressive disease, increasing odds of worsening endoscopic severity despite therapy escalation by ∼4.6 during follow-up, thereby linking early stromal biology to clinical endpoints. Unlike QMFs, IMFs exhibited a senescence-associated secretory phenotype that impaired epithelial stemness, barrier integrity, and innate immune fitness. State-guided prioritization identified EDNRB-antagonism as a high-confidence stromal intervention, reversing pathogenic phenotypes across orthogonal assays and species. Outcome simulation positioned stromal-state reversibility by EDNRB-antagonism as a precision axis, reducing odds of recalcitrance by ∼96.4% and reframing treatment resistance as a reversible stromal state.
    Graphic Abstract: In this work, Tindle et al. identify reversible stromal states that govern recalcitrant IBD and nominate precision reprogramming of pathogenic myofibroblasts as a new therapeutic strategy.
    DOI:  https://doi.org/10.64898/2026.05.01.720931
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒25 at 14:41.