bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–07–12
nineteen papers selected by
Xiao Qin, University of Oxford
  1. Spatial multi-omics landscape of colorectal cancer macro- and micrometastases.
  2. Progressive intestinal tumor cell plasticity, Myc activation, and loss of Lgr5+ tumor stem cell lineage commitment upon Wnt depletion.
  3. SpatioTemporal Omics Consortium: a global effort for biological discovery across species, space and time.
  4. Tissue mechanopathology of cancer.
  5. Bridging omics and physiology to build multimodal clocks of human aging.
  6. Myeloid-derived suppressor cells in colorectal cancer: mechanisms of immunosuppression, therapy resistance and therapeutic targeting.
  7. Autonomous biomedical research with an artificial intelligence agent.
  8. Which 'AI scientist' suits your lab? A guide for the perplexed.
  9. Universal cell embedding provides a foundation model for cell biology.
  10. Macrophage-Induced Senescent Cancer-Associated Fibroblasts Promote SASP-Mediated Chemoresistance in Colorectal Cancer.
  11. Activation of KIT signaling promotes early tumorigenesis through the AP-1 pathway in APC/TP53 double-knockout human colon organoids.
  12. Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses.
  13. Interpreting the genetic basis of inflammatory bowel disease.
  14. Evolving patterns of co-mutations from tumor initiation to metastatic progression.
  15. Biological aging clocks in health and disease.
  16. How to advance revolutionary science: high turnover, high risk and a licence to fail.
  17. Your neighbors matter: Adjacent cancer cells dampen TLS function.
  18. Mapping the path to clinical implementation of multi-omics.
  19. A Simple, Cost-Effective, High-Throughput Method for Measuring Chromatin Accessibility and Gene Expression in Single Nuclei.
  1. Cancer Cell. 2026 Jul 09. pii: S1535-6108(26)00296-5. [Epub ahead of print]
    Spatial multi-omics landscape of colorectal cancer macro- and micrometastases.
    Yang Liu, Akshaya S Jadhav, Yuwen Pan, Jianlong Liao, Isha Khanduri, Yunhe Liu, Riham Katkhuda, Wei Lu, Kyung Serk Cho, Zhimin Tong, Tieling Zhou, Kangyu Lin, Baohua Sun, Mei Jiang, Sharia D Hernandez, Idania Carolina Lubo Julio, Patrick Brennan, Guangsheng Pei, Kai Yu, Yibo Dai, Tian Chu, Fuduan Peng, Khaja Khan, Saxon Rodriguez, Ling Xia, Youming Guo, Alicia Mejia, Sean W Barnes, Ou Shi, Shreeya Indulkar, Alaa M T Mohamed, Natalie Wall Fowlkes, Timothy Newhook, Yun Shin Chun, Van K Morris, David Menter, Dadi Jiang, John Paul Shen, Ryan Sun, Jean-Nicolas Vauthey, Ruoyan Li, Humam Kadara, Luisa M Solis Soto, Scott Kopetz, Linghua Wang, Dipen Maru.
      Colorectal cancer (CRC) metastases frequently recur due to minimal residual disease (MRD) and persistent micrometastases after therapy. Here, we performed spatial multimodal profiling using spot-level and high-resolution spatial transcriptomics, multi-regional whole-genome sequencing following laser-capture microdissection, and high-plex protein imaging to map 49 tumors from 19 patients, encompassing paired primary CRC and matched liver (CLiM) and lung (CLuM) metastases. Phylogenetic reconstruction revealed that liver micrometastases (CLiMi) arose from early clonal divergences and harbored a stem-like, quiescent state consistent with metastatic dormancy. Spatially, we uncovered distinct stromal barriers: macrometastases were encapsulated by myofibroblasts, whereas micrometastases were surrounded by immunosuppressive niches characterized by T cell exhaustion and distinct ligand-receptor signaling networks. Notably, we identified a CLiMi-specific six-gene signature associated with MRD status, disease-free survival, and chemotherapy resistance across multiple independent cohorts. These findings elucidate the spatial evolutionary landscape of CRC metastases and provide tissue-based spatially validated biomarkers for surveillance and therapeutic targeting.
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.009
  2. Sci Adv. 2026 Jul 10. 12(28): eaeb8564
    Progressive intestinal tumor cell plasticity, Myc activation, and loss of Lgr5+ tumor stem cell lineage commitment upon Wnt depletion.
    Marika Lassila, Fatemeh Seyednasrollah, Cinzia Bessone, Maritta Räisänen, Inkeri Vuori, Davide G Berta, Johanna Aspholm, Tatiana V Petrova, Lauri A Aaltonen, Kari Alitalo, Pauliina Kallio.
      Plasticity, the capability of tumor cells to go through phenotypic transitions, promotes colorectal cancer (CRC) progression and treatment resistance. Although plasticity is evident in advanced CRCs, little is known about plasticity in early-stage tumors and tumor stem cells. Here, we demonstrate that a plastic cell state (PCS) is present already in polyps from patients with familial adenomatous polyposis and in mouse intestinal adenomas, in which PCS is associated with PROX1+ tumor stem cells. We furthermore analyzed progressive plasticity upon loss of the canonical wingless-related integration site (Wnt) effector Tcf7 or Lef1 in Apc mutant mice. Deletion of either gene led to emergence of new plastic tumor cell populations, failure of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) tumor stem cell differentiation into enterocyte-like cells, enhanced Myc pathway activation, and increased tumor cell proliferation and tumorigenesis. Together, we demonstrate that PCS is associated with early CRC development and identify multiple potentially druggable mechanisms activated during progressive tumor cell plasticity.
    DOI:  https://doi.org/10.1126/sciadv.aeb8564
  3. Nat Methods. 2026 Jul 09.
    SpatioTemporal Omics Consortium: a global effort for biological discovery across species, space and time.
    Lipin Loo, Keke Xia, Nicola Crosetto, Magda Bienko, Chang Xu, Jinmiao Chen, Anna Pascual Reguant, Chengyu Li, Ji Wang, Xiaofeng Wei, Longqi Liu, Shiping Liu, Lei Han, Ivano Legnini, Craig Glastonbury, Alok Sharma, Yutaka Suzuki, Nir Yosef, Boxiang Liu, Grace Yeo, Mu-Ming Poo, Holger Heyn, Fabian Theis, Partha Majumder, Jan Mulder, Ido Amit, Piero Carninci, Xun Xu, Weibin Liu, Quan Nguyen.
      
    DOI:  https://doi.org/10.1038/s41592-026-03150-6
  4. Dev Cell. 2026 Jul 08. pii: S1534-5807(26)00230-3. [Epub ahead of print]61(7): 1392-1406
    Tissue mechanopathology of cancer.
    Johanna Ivaska, Sarah Sale, Alpha S Yap.
      Cancers are complex cellular communities comprising tumor cells and their microenvironment. Recent advances in cancer biology have emerged from efforts to analyze tumors as tissues, in which emergent properties arise as tumor cells interact with one another, their microenvironment, and the host tissue. In this review, we consider interactions involving mechanical forces and mechanosignaling pathways that detect changes in physical inputs to regulate cellular behavior. This rapidly developing field provides perspectives for understanding cancer biology and tumor interactions with the host ecosystem.
    DOI:  https://doi.org/10.1016/j.devcel.2026.06.006
  5. Cell. 2026 Jul 09. pii: S0092-8674(26)00705-1. [Epub ahead of print]189(14): 4190-4192
    Bridging omics and physiology to build multimodal clocks of human aging.
    Seda Koyuncu, Dunja Petrovic, David Vilchez.
      Human aging is a heterogeneous, multi-system process that spans molecular, tissue, and physiological decline. In this issue of Cell, Li et al. integrate clinical data, multi-omics, and organ-associated signatures to construct a multi-layer framework for quantifying biological aging across scales.
    DOI:  https://doi.org/10.1016/j.cell.2026.06.018
  6. Front Cell Dev Biol. 2026 ;14 1840613
    Myeloid-derived suppressor cells in colorectal cancer: mechanisms of immunosuppression, therapy resistance and therapeutic targeting.
    Haoyi Zhang, Wenyue Liu, Yutong Zhang, Shuchen Chen, Gongping Sun.
      The overall response of colorectal cancer (CRC) to immune checkpoint blockade remains limited, particularly in patients with microsatellite-stable disease. One important underlying mechanism is the involvement of myeloid-derived suppressor cells (MDSCs) in shaping an immunosuppressive TME. Under the influence of tumor-associated genetic alterations, chronic inflammation, the intestinal microbiota, metabolic stress, and therapeutic pressure, MDSCs undergo aberrant expansion and functional skewing. By remodeling the local immune ecology, they attenuate T cell- and natural killer (NK) cell-mediated antitumor responses. Concurrently, MDSCs are also implicated in angiogenesis, barrier disruption, stromal remodeling, premetastatic niche formation, and therapeutic tolerance. Thus, MDSCs are not only critical mediators of immune evasion but also key components of CRC progression and treatment resistance. Current clinical translation in this field remains constrained by the ambiguous definition of human MDSCs, phenotypic overlap, insufficient functional validation, and imprecise patient stratification. Future studies should integrate single-cell omics, spatial omics, metabolic profiling, and microbiome analyses to establish more functionally oriented biomarkers. On this basis, combination therapeutic strategies targeting MDSC recruitment, suppressive function, or reprogramming states should be further developed.
    Keywords:  colorectal cancer; immune checkpoint blockade; immunotherapy resistance; myeloid-derived suppressor cells; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1840613
  7. Science. 2026 Jul 09. eadz4351
    Autonomous biomedical research with an artificial intelligence agent.
    Kexin Huang, Serena Zhang, Hanchen Wang, Yuanhao Qu, Yingzhou Lu, Ryan Li, Yusuf Roohani, Lin Qiu, Shiyi Cao, Gavin Li, Junze Zhang, Di Yin, Rick Wierenga, Deniz Kavi, Sherry Liu, Tianwei She, Shruti Marwaha, Jennefer N Carter, Xin Zhou, Matthew T Wheeler, Jonathan A Bernstein, Mengdi Wang, Peng He, Jingtian Zhou, Michael P Snyder, Le Cong, Aviv Regev, Jure Leskovec.
      Biomedical research is increasingly constrained by repetitive, fragmented workflows that slow discovery. We introduce Biomni, a general-purpose biomedical artificial intelligence agent that autonomously executes diverse research tasks. To map the biomedical action space, Biomni's action-discovery agent mines tools, databases, and protocols from thousands of publications across 25 domains, building a unified agentic environment. Its general-purpose architecture integrates large language model reasoning with retrieval-augmented planning and code-based execution, dynamically composing workflows without predefined templates. Systematic benchmarking shows strong generalization across heterogeneous tasks-causal gene prioritization, drug repurposing, rare-disease diagnosis, microbiome analysis, and molecular cloning-without task-specific tuning. Real-world case studies demonstrate Biomni interpreting multi-modal datasets, optimizing protein stability, orchestrating wet-lab instruments, and generating experimentally testable protocols. Biomni envisions artificial intelligence augmenting human scientists and accelerating discovery.
    DOI:  https://doi.org/10.1126/science.adz4351
  8. Nature. 2026 Jul 10.
    Which 'AI scientist' suits your lab? A guide for the perplexed.
    Ewen Callaway.
      
    Keywords:  Computational biology and bioinformatics; Machine learning
    DOI:  https://doi.org/10.1038/d41586-026-02091-6
  9. Nature. 2026 Jul 08.
    Universal cell embedding provides a foundation model for cell biology.
    Tabula Sapiens Consortium
      Developing a universal representation space for cells that encompasses the tremendous molecular diversity of cell types across species would be transformative for cell biology. Recent work using single-cell transcriptomic approaches to create molecular definitions of cell types in the form of cell atlases has provided the necessary data for such an endeavour1-3. Here we present the universal cell embedding (UCE) foundation model. UCE was trained on a large corpus of cell data using self-supervision, creating a unified biological latent space that can represent cells across diverse tissues and species. This latent space captures important biological variation despite the presence of experimental noise. UCE's universality means that new cells can be embedded with no data labelling, model training or fine-tuning. We used UCE to create the Integrated Mega-scale Atlas, embedding 36 million cells, with more than 1,000 uniquely named cell types, from hundreds of experiments, dozens of tissues and eight species. We gain insights into the organization of cell types and tissues within the space. UCE's embedding space exhibits emergent behaviour, identifying biology that it was never trained for, such as identifying developmental lineages and embedding data from species that were not included in the training set. Overall, by enabling a universal representation for every cell state and type, UCE is a valuable tool for analysis, annotation and hypothesis generation over single-cell data.
    DOI:  https://doi.org/10.1038/s41586-026-10689-z
  10. Cancer Res. 2026 Jul 08.
    Macrophage-Induced Senescent Cancer-Associated Fibroblasts Promote SASP-Mediated Chemoresistance in Colorectal Cancer.
    Shuaixi Yang, Yukang Chen, Shutong Liu, Anning Zuo, Yuhao Ba, Yuyuan Zhang, Benyu Liu, Chuhan Zhang, Hui Xu, Peng Luo, Quan Cheng, Siyuan Weng, Long Liu, Xing Zhou, Teng Pan, Ruijie Ming, Jingyuan Ning, Xin Hu, Xinwei Han, Fubing Wang, Jinhai Deng, Zaoqu Liu.
      Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment (TME) by influencing tumor progression, metastasis, and therapy resistance. Accumulating evidence suggests that CAFs undergo senescence, which can impact their effects on the TME. Here, we developed a machine learning-based prediction model, the Cellular Senescence Prediction Model (CSPM), to accurately identify senescent CAFs (sCAFs) based on single-cell RNA sequencing data. In colorectal cancer (CRC), the abundance of sCAFs strongly correlated with impaired chemotherapy responsiveness and poor prognosis. In preclinical models, including subcutaneous tumors, patient-derived organoids (PDOs), patient-derived organoid xenografts (PDOXs), and orthotopic tumors, sCAFs mediated chemoresistance through the senescence-associated secretory phenotype (SASP), with IL6 and CXCL12 being key contributors. Macrophage-derived IL1B triggered CAF senescence through the IL1B-IL1R1 interaction, promoting the accumulation of sCAFs in tumors. Spatial transcriptomics and multiplex immunohistochemistry revealed colocalization of IL1B+ macrophages and IL1R1+ sCAFs in the tumor stroma. Functional studies using fibroblast-specific Il1r1 knockout mice further confirmed that macrophage-derived IL1B induces CAF senescence via IL1R1, leading to SASP-driven chemotherapy resistance. These findings highlight the critical role of sCAFs in CRC chemoresistance and suggest that targeting the IL1B-IL1R1 axis may offer a promising strategy to enhance chemotherapy efficacy in CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4870
  11. Cell Death Dis. 2026 Jul 04.
    Activation of KIT signaling promotes early tumorigenesis through the AP-1 pathway in APC/TP53 double-knockout human colon organoids.
    Younghee Choi, Eunju Kim, Soo-Yeon Cho, Jihyun Park, Youngwon Cho, Sungho Kim, Sang-Hyun Song, Tae-You Kim.
      Colorectal cancer (CRC) develops through a series of progressive genetic mutations, with alterations in APC and TP53 being the most frequently observed in the early stages. Although the loss of APC is recognized as a significant initiating event, the epigenetic processes through which the simultaneous inactivation of APC and TP53 facilitates the onset of colorectal tumorigenesis remain poorly characterized. To address this gap, we developed a human colon organoid model using CRISPR-Cas9 to achieve a double knockout of APC and TP53. Through extensive multi-omics profiling, we characterized the epigenetic landscape distinctive of early-stage CRC. We identified KIT, a receptor tyrosine kinase, as a critical oncogenic driver that is significantly upregulated in ΔDKO (APC and TP53 double knockout) organoids, thereby activating the MAPK and Wnt signaling pathways to augment proliferation and tumorigenesis. Furthermore, AP-1 transcription factors (FOS/JUN) regulate KIT expression via chromatin remodeling. Functional analyses indicated that KIT is integral to sustaining the elevated proliferation rates observed in ΔDKO organoids. These findings reveal a novel AP-1/KIT signaling axis that is central to the early progression of CRC, thereby presenting a promising avenue for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41419-026-09056-7
  12. bioRxiv. 2026 Jul 04. pii: 2026.06.30.735606. [Epub ahead of print]
    Colorectal cancers with distinct metastatic potential trigger divergent early T cell responses.
    Marwa Saad, Alexandra Thoms, Yue S Yin, Izabela Mamede, Afsana Rahman, Ruonan Chen, Sebastián E Carrasco, Patrick W Darcy, Norihiro Goto, Sohail F Tavazoie, Angelina M Bilate, Daniel Mucida.
      Colorectal cancer (CRC) remains a leading cause of cancer mortality, with most cases refractory to immunotherapy. Distinguishing tumor-induced from steady-state mucosal T cell responses has been a critical barrier to understanding antitumor immunity in CRC. Using orthotopic transplantation of CRC organoids with and without metastatic potential, combined with temporal T cell fate-mapping, we show that non-metastatic tumors elicit early recruitment of CD8αβ⁺ and CD4⁺ T cells that acquired cytotoxic and Th1-like programs, whereas pro-metastatic tumors induce a naïve-like, hypoactivated state. Tumor-infiltrating CD4 + T cells underwent clonal expansion, including clones recognizing microbial and dietary antigens. T cells in physical contact with tumor cells, identified by uLIPSTIC, were enriched for expanded and cytotoxic clones. Fate-mapped T cells from non-metastatic tumors suppressed tumor growth in an IFN-γ-dependent manner, whereas pro-metastatic tumor-derived T cells failed to do so. Mechanistically, pro-metastatic tumors downregulated MHCII, and Ciita targeting in non-metastatic organoids reduced CD4⁺ clonal expansion and led to tumor progression. Together, these findings define divergent early T cell trajectories associated with CRC metastatic potential, indicating that ineffective local immune engagement precedes metastatic dissemination.
    DOI:  https://doi.org/10.64898/2026.06.30.735606
  13. Nat Genet. 2026 Jul 10.
    Interpreting the genetic basis of inflammatory bowel disease.
    Margot Brandt.
      
    DOI:  https://doi.org/10.1038/s41588-026-02700-0
  14. Nat Genet. 2026 Jul 10.
    Evolving patterns of co-mutations from tumor initiation to metastatic progression.
    Arvind Iyer, Miljan Petrovic, Debora Sesia, Luca Nanni, Marco Mina, Giovanni Ciriello.
      Phenotypically healthy cells frequently harbor somatic variants at cancer-associated genes, indicating that malignant transformation requires the selection of several alterations. Predicting which combinations of mutations, or co-mutations, exhibit oncogenic capacity requires identifying co-mutations that occur more or less frequently than expected. However, statistical frameworks to solve this problem are hampered by tumor heterogeneity and data availability. Here we curated putative oncogenic mutations in >70,000 human tumors from 119 subtypes, and designed a strategy to search for co-mutations based on in silico simulation of mutagenesis (SelectSim). Using this dataset and tool, we discovered and validated co-mutations across independent human cohorts, compared co-mutations across different tumor types and identified potential risk factors of metastatic progression. Notably, across several cohorts of phenotypically normal tissue samples, we show that, unlike individual oncogenic variants, significantly co-occurring mutations are largely cancer-specific and are observed rarely in healthy tissues, providing clues about the paths to tumorigenesis.
    DOI:  https://doi.org/10.1038/s41588-026-02661-4
  15. Nat Med. 2026 Jul 09.
    Biological aging clocks in health and disease.
    Tony Wyss-Coray, Eric J Topol.
      There are extensive ongoing efforts to slow or even reverse human aging, such as with epigenetic cellular reprogramming, thymus rejuvenation or senolytics. In parallel, new and diverse metrics-known as biological clocks-have been discovered and shown to track the pace of aging in an individual and their organs, tissues and cells. These clocks have multiple potential use cases, including identifying people at high risk of disease, serving as a foundation for prevention or early detection, and determining whether lifestyle factors or an intervention can modulate the aging process. This review provides a critical appraisal of the progress that is being made with biological clocks and how they might ultimately help understand pathobiology, reduce the burden of disease and extend healthspan.
    DOI:  https://doi.org/10.1038/s41591-026-04495-3
  16. Nature. 2026 Jul 08.
    How to advance revolutionary science: high turnover, high risk and a licence to fail.
    Elizabeth Gibney.
      
    Keywords:  Funding; Government
    DOI:  https://doi.org/10.1038/d41586-026-02090-7
  17. Cancer Cell. 2026 Jul 09. pii: S1535-6108(26)00298-9. [Epub ahead of print]
    Your neighbors matter: Adjacent cancer cells dampen TLS function.
    Nicholas J Salgia, Jason B Muhitch.
      In this issue of Cancer Cell, Hernández-Verdin et al. reveal why some tumors with tertiary lymphoid structures (TLSs) resist immunotherapy: their findings identify cancer-derived gamma-aminobutyric acid (GABA) as an immunosuppressant factor resulting in dysfunctional TLS and immunotherapy resistance. Targeting GABA with immunotherapy reshapes the tumor and TLS microenvironment and ultimately improves therapeutic efficacy.
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.011
  18. Nat Genet. 2026 Jul 07.
    Mapping the path to clinical implementation of multi-omics.
    Said I Ismail, Chadi Saad, Mohamed A Elrayess, Ahmad A L Khleifat, Nagham Nafiz Hendi, Yasser AlSarraj, Radja Messai Badji, Wadha A A L Muftah.
      Multi-omics promises to transform medicine by providing holistic disease insights through interacting molecular layers, involving DNA, RNA, proteins and metabolites. The underlying technologies have matured rapidly, currently enabling higher throughputs at lower costs. Yet as multi-omics moves from research to routine care, the central challenge is no longer data generation, but standardizing and interpreting complexity within health systems built for discrete tests. In this Perspective, we chart the path from assay to implementation by demonstrating how integrative analyses outperform single modalities, as well as by emphasizing that multiplexing, high dimensionality and probabilistic interpretation introduce risks to reproducibility and clinical validity. We examine computational strategies for multimodal integration, highlighting the importance of explainable AI for auditability and regulatory trust. Drawing on lessons from early national programs, we suggest that scalable clinical adoption depends on interoperable digital infrastructures, harmonized quality standards and multidisciplinary care models that embed multi-omics into everyday practice.
    DOI:  https://doi.org/10.1038/s41588-026-02663-2
  19. bioRxiv. 2026 Jun 30. pii: 2026.06.29.735326. [Epub ahead of print]
    A Simple, Cost-Effective, High-Throughput Method for Measuring Chromatin Accessibility and Gene Expression in Single Nuclei.
    Zhifei Luo, William J Greenleaf.
      We describe microfluidic-free, droplet-based methods for single-nucleus epigenomic measurements: Particle-templated Instant Partition single-nucleus assay for transposase-accessible chromatin using sequencing (PIP-ATAC-seq) and its multiomic version (PIP-Multiome-seq). We benchmarked these assays by generating data sets containing thousands of nuclei using cell lines and mouse brains and compared to other established methods. PIP-Multiome and PIP-ATAC are straightforward to implement, affordable, and produce high-quality data, providing useful additions to the single-cell molecular measurement armamentarium.
    DOI:  https://doi.org/10.64898/2026.06.29.735326
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒27 at 16:07.