bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–02–08
24 papers selected by
Xiao Qin, University of Oxford
  1. Interpretable data integration for single-cell and spatial multi-omics.
  2. Scaling perturbations: beyond genome-scale CRISPR screens.
  3. Regulatory grammar in human promoters uncovered by MPRA-based deep learning.
  4. Integrative Inference of Spatially Resolved Cell Lineage Trees using LineageMap.
  5. Hallmarks of cancer-Then and now, and beyond.
  6. Notch3 regulates pericyte phenotypic plasticity in colorectal cancer.
  7. Leveraging multi-modal foundation models for analysing spatial multi-omic and histopathology data.
  8. CCL3 is produced by aged neutrophils across cancers and promotes tumor growth.
  9. Reliable detection of Host-Microbe Signatures in cancer using PRISM.
  10. MultiSP deciphers tissue structure and multicellular communication from spatial multi-omics data.
  11. The role of Fusobacterium nucleatum in the tumour microenvironment and carcinogenesis of oral and colonic malignancies.
  12. Atlas-guided discovery of transcription factors for T cell programming.
  13. Emerging landscape of KRAS inhibitors in cancer treatment.
  14. Addressing current limitations of colonoscopy for colorectal cancer screening.
  15. Plasticity as Resistance: KRAS Inhibition Reveals WNT Adaptation in Metastatic Colorectal Cancer.
  16. The Spatiotemporal Heterogeneity of Tumor-Associated Stromal Cells: Reprogramming Plasticity to Unlock Precision Cancer Immunotherapy.
  17. More than one-third of cancer cases are preventable, massive study finds.
  18. Lymph node colonization induces tissue remodeling via immunosuppressive fibroblast-myeloid cell niches supporting metastatic tolerance.
  19. Patient-derived models of tumor-immune cell interactions.
  20. Biophysical approaches to cancer diagnostics: Collagen biomarkers in colorectal cancer.
  21. TISSUE-SPECIFIC SPATIAL REGULATION OF INNATE IMMUNE CHECKPOINTS IN CANCER.
  22. Rising Star: Single cell omics technologies: when whole omics analysis meets single cell resolution.
  23. Shifting paradigms in tissue stem cell biology: Insights from the intestine.
  24. Re-evaluating population-level screening recommendations to address increasing early-onset colorectal cancer rates in Australia: a modelling study.
  1. Cell Syst. 2026 Feb 04. pii: S2405-4712(25)00312-6. [Epub ahead of print] 101479
    Interpretable data integration for single-cell and spatial multi-omics.
    Chenghui Yang, Zhentao He, Qing Nie, Lihua Zhang.
      Integrating single-cell or spatial transcriptomic and epigenomic data enables scrutinizing the transcriptional regulatory mechanisms controlling cell fate. Current integration methods usually align multi-omics data into a shared latent space but fail to reveal the underlying connections between genes and regulatory elements. The correlation- or regression-based regulatory inference methods cannot dissect different transcriptional regulation codes for cells under different spatial and temporal states. To address both problems, we develop a feature-guided optimal transport (FGOT) method, which simultaneously uncovers cellular heterogeneity and their associated transcriptional regulatory links. FGOT also provides post hoc interpretability for existing integration methods. FGOT is applicable for paired/unpaired single-cell multi-omics data and paired spatial multi-omics data. Benchmarking and validating via histone modification data or three-dimensional (3D) genomics data show good robustness and accuracy in integration and inference of regulatory links. The method allows systematic screening of cell-state and spatial-location-specific regulatory elements in diseases at the single-cell level. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  multi-omics integration; optimal transport; single cell; spatial genomics; transcriptional regulatory
    DOI:  https://doi.org/10.1016/j.cels.2025.101479
  2. bioRxiv. 2026 Jan 17. pii: 2026.01.16.699948. [Epub ahead of print]
    Scaling perturbations: beyond genome-scale CRISPR screens.
    Anran Tang, Rico C Ardy, Rafaela E Mendes, Thomas M Norman.
      CRISPR screens have become essential tools for systematically probing gene function from basic biology to drug discovery, yet important frontiers remain beyond genome scale. Probing regulatory elements, interpreting genetic variants, and mapping genetic interactions all challenge the sensitivity and scalability of existing approaches. Here we introduce two synergistic technologies to address these limitations. PORTAL (Perturbation Output via Reporter Transcriptional Activity in Lineages) shifts pooled genetics toward quantitative RNA phenotypes, encoding perturbation effects in expressed transcripts to enable single-molecule measurements with lineage or single-cell resolution. CAP cloning (Covalently closed Assembly Products) bypasses bacterial transformation to enable construction of ultrahigh-complexity lentiviral libraries. Combining these advances, we construct a genetic interaction map spanning 665,856 pairwise perturbations across 46 million clonal lineages-the largest exhaustive map in human cells and the first at this scale using a non-fitness phenotype. More broadly, this work charts a path toward comprehensive genetic interaction mapping in human cells.
    DOI:  https://doi.org/10.64898/2026.01.16.699948
  3. Nature. 2026 Feb 04.
    Regulatory grammar in human promoters uncovered by MPRA-based deep learning.
    Lucía Barbadilla-Martínez, Noud Klaassen, Vinícius H Franceschini-Santos, Jérémie Breda, Hatice Yücel, Miguel Hernández-Quiles, Tijs van Lieshout, Carlos G Urzua Traslaviña, Minh Chau Luong Boi, Maryam Akbarzadeh, Celia Hermana-Garcia-Agullo, Sebastian Gregoricchio, Marcel de Haas, Roy Straver, Sarah Derks, Wilbert Zwart, Emile Voest, Lude Franke, Michiel Vermeulen, Jeroen de Ridder, Bas van Steensel.
      Promoters are the core regulatory elements of all genes. Their activity ensures the correct transcription level of each individual gene, which is essential for cellular homeostasis and responses to a wide range of signals. One of the major challenges in genomics is to build computational models that accurately predict genome-wide gene expression from the sequences of regulatory elements1. Here we present promoter activity regulatory model (PARM), a cell-type-specific deep-learning model trained on specially designed massively parallel reporter assays (MPRAs) that query human promoter sequences. PARM is experimentally and computationally lightweight so that cell-type-specific and condition-specific models can be generated that reliably predict autonomous promoter activity across the genome from the DNA sequence alone. PARM can also design purely synthetic strong promoters. We leveraged PARM to systematically identify binding sites of transcription factors that probably contribute to the activity of each natural human promoter and to detect the rewiring of these regulatory interactions after various stimuli to the cells. We also uncovered and experimentally confirmed substantial positional preferences of transcription factors that differ between activating and repressive regulatory functions and a complex grammar of motif-motif interactions. Our approach provides a highly economic strategy towards a deeper understanding of the dynamic regulation of human promoters by transcription factors.
    DOI:  https://doi.org/10.1038/s41586-025-10093-z
  4. bioRxiv. 2026 Jan 22. pii: 2026.01.19.700383. [Epub ahead of print]
    Integrative Inference of Spatially Resolved Cell Lineage Trees using LineageMap.
    Xinhai Pan, Yiru Chen, Xiuwei Zhang.
      Understanding the spatio-temporal processes of tissue growth, including how new cell types emerge and how cells form the tissue architecture, is a fundamental problem in biology. The emerging spatially resolved lineage tracing data, where three modalities, lineage barcodes, gene expression profiles, and spatial locations, are measured for each single cell, provides an unprecedented opportunity to understand these processes. Computational methods that take advantage of all three modalities to reconstruct cell lineage tree and ancestral cell states and locations are needed. We introduce LineageMap, a hybrid lineage inference algorithm that integrates the scalability of distance-based tree reconstruction methods with the flexibility of likelihood-based methods under a unified probabilistic framework. The input to LineageMap is spatially resolved lineage tracing data, where for each single cell, the gene expression, lineage barcode and spatial locations are available. LineageMap enables accurate, interpretable, and scalable inference of high-resolution lineage trees as well as locations of ancestral cells from the tri-modality single-cell data. Across simulated and experimental datasets, LineageMap consistently outperforms existing methods in the accuracy of reconstructed cell lineage trees, while revealing biologically coherent spatiotemporal trajectories. Our framework bridges molecular lineage tracing with spatial and transcriptomic information, advancing computational reconstruction of dynamic cellular ancestries in both time and space. LineageMap is available at: https://github.com/ZhangLabGT/LineageMap .
    DOI:  https://doi.org/10.64898/2026.01.19.700383
  5. Cell. 2026 Jan 29. pii: S0092-8674(25)01498-9. [Epub ahead of print]
    Hallmarks of cancer-Then and now, and beyond.
    Douglas Hanahan.
      Cancer presents a remarkably instructive perturbation of mechanisms manifesting in our biology that have gone awry, eliciting a malady that is inexorably increasing in incidence and societal burden concomitant with healthier aging. The wealth of knowledge and data forthcoming from decades of cancer research can be organized into conceptually distinct but interconnected parametric dimensions that define the mechanistic foundation of the disease: aberrantly acquired functional capabilities (the hallmarks of cancer), enabling phenotypic characteristics, hallmark-conveying cells populating cancer microenvironments, and systemic interactions. Collectively, they provide a logical framework with which to illuminate the operating systems of these outlaw organs, from inception through multistage tumorigenesis to adaptive evolution. This review presents a concise synthesis of the hallmark conceptualization as it has been refined during the past 25 years, including a corollary hypothesis that mechanism-guided hallmark co-targeting could offer impactful new therapeutic strategies for treating human cancers.
    DOI:  https://doi.org/10.1016/j.cell.2025.12.049
  6. Commun Biol. 2026 Jan 30.
    Notch3 regulates pericyte phenotypic plasticity in colorectal cancer.
    Niki Chalkidi, Athanasia Stavropoulou, Vasiliki-Zoi Arvaniti, Christina Paraskeva, Artemis Monogyiou, Maria Sakkou, Christoforos Nikolaou, Vasiliki Koliaraki.
      Pericytes, essential components of the tumor microenvironment, undergo phenotypic alterations that influence cancer progression, yet the molecular mechanisms governing these changes remain poorly understood. Here, we investigate the role of Notch3 signaling in pericyte phenotype and functions in colorectal cancer (CRC). Using lineage tracing approaches, we show that murine tumor pericytes originate from normal tissue-resident pericytes, which proliferate inside tumors. In vivo genetic manipulation reveals that Notch3 pathway activation promotes pericyte proliferation, while suppressing contractile protein expression, and leads to increased endothelial cell proliferation and reduced blood vessel integrity. In contrast, Notch3 deletion leads to decreased endothelial proliferation, blood vessel normalization, and a significant reduction in tumorigenesis in an advanced orthotopic mouse model. Single-cell RNA sequencing analysis uncovers significant pericyte heterogeneity in both mouse colitis-associated cancer and human CRC. It specifically identifies distinct subpopulations characterized by differential Notch3 activity, which is enriched in a synthetic subset and absent in a contractile subset, further supporting our in vivo findings. Our results establish Notch3 as a key regulator of pericyte phenotypic plasticity in CRC and suggest that targeting this pathway could represent a promising strategy for improving therapeutic outcomes through vascular normalization.
    DOI:  https://doi.org/10.1038/s42003-026-09629-4
  7. Nat Biomed Eng. 2026 Feb 05.
    Leveraging multi-modal foundation models for analysing spatial multi-omic and histopathology data.
    Tianyu Liu, Tinglin Huang, Tong Ding, Hao Wu, Peter Humphrey, Sudhir Perincheri, Kurt Schalper, Rex Ying, Hua Xu, James Zou, Faisal Mahmood, Hongyu Zhao.
      Recent advances in pathology foundation models, pre-trained on large-scale histopathology images, have greatly advanced disease-focused applications. At the same time, spatial multi-omic technologies now measure gene and protein expression with high spatial resolution, offering valuable insights into tissue context. Yet, existing models struggle to integrate these complementary data types. Here, to address this challenge, we present spEMO, a computational framework that unifies embeddings from pathology foundation models and large language models for spatial multi-omic analysis. By leveraging multi-modal representations, spEMO surpasses single-modality models across diverse downstream tasks, including spatial domain identification, spot-type classification, whole-slide disease prediction and interpretation, multicellular interaction inference and automated medical reporting. These results highlight spEMO's strength in both biological discovery and clinical applications. Furthermore, we introduce a new benchmark task-multi-modal alignment-to evaluate how effectively pathology foundation models retrieve complementary information. Together, spEMO establishes a powerful step towards holistic, interpretable and generalizable AI for spatial biology and pathology.
    DOI:  https://doi.org/10.1038/s41551-025-01602-6
  8. Cancer Cell. 2026 Feb 05. pii: S1535-6108(26)00045-0. [Epub ahead of print]
    CCL3 is produced by aged neutrophils across cancers and promotes tumor growth.
    Evangelia Bolli, Pratyaksha Wirapati, Mehdi Hicham, Yuxuan Xie, Marie Siwicki, Florent Duval, Anne-Gaëlle Goubet, Máté Kiss, Béatrice Zitti, Thomas Zwahlen, Sheri Mcdowell, Ruben Bill, Simona Angerani, Camilla Engblom, Seth Anderson, Aiping Jiang, Oliver Hartley, David B Sykes, Maja Jankovic, Nadine Fournier, Matthias Gunzer, David Tarussio, Stéphanie Tissot, Peter M Sadow, William C Faquin, Moshe Sade-Feldman, Ralph Weissleder, Sara Pai, François Mercier, Robert Manguso, Mikaël J Pittet.
      Tumor-associated neutrophils (TANs) are abundant across cancers, yet their phenotypic diversity and functional states remain poorly defined. Here, we introduce a cell-type probability classifier that recovers low-transcript neutrophils from scRNAseq datasets, enabling pan-cancer analyses of TAN heterogeneity. Across >190 human and murine tumors, we identify a conserved differentiation trajectory that culminates in a terminal CCL3hi state. This state exhibits pro-tumor transcriptional programs, including those involved in hypoxic adaptation and senescence. Consistently, CCL3hi TANs are enriched in hypoxic tumor niches in both humans and mice. Through mechanistic perturbations of neutrophil-derived CCL3 in mice, we show that it sustains TAN survival in hypoxic tumor regions via CCR1-dependent signaling. These findings establish CCL3 as a conserved marker and functional driver of pro-tumor neutrophils in growing tumors, and provide a scalable framework for dissecting neutrophil biology across cancer types.
    Keywords:  CCL3-CCR1 signaling; CRISPR perturbation; hypoxia; neutrophil aging; neutrophil differentiation; neutrophil heterogeneity; pan-cancer analysis; single-cell RNA sequencing; tumor microenvironment; tumor-promoting neutrophils
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.006
  9. Cancer Cell. 2026 Feb 05. pii: S1535-6108(26)00046-2. [Epub ahead of print]
    Reliable detection of Host-Microbe Signatures in cancer using PRISM.
    Bassel Ghaddar, Martin J Blaser, Subhajyoti De.
      Recent controversy in the cancer microbiome field highlights the need for more reliable microbial detection from human genomic data. Here, we develop PRISM, an efficient computational framework for precise microorganism identification and decontamination from low-biomass sequencing data. PRISM achieves robust performance when benchmarked on 230 independent datasets with known true-positive and contaminant taxa. We then use PRISM to profile 25 cancer types from The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium. We identify consistent microbial signatures in gastrointestinal tract, head-and-neck, and urogenital tract tumors, and sparse signal elsewhere. In pancreatic cancer, we associate microbial detection with altered host protein glycosylation pathways and greater smoking exposure. Lastly, we consider the impact of sequencing approaches on positive and negative data interpretation. Overall, PRISM improves the reliability of microbial profiling and allows leveraging of existing human genomic data for the concurrent detection of host-microbial signatures with potential molecular and clinical significance.
    Keywords:  cancer; contamination; machine learning; microbiome; sequencing
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.007
  10. Cell Genom. 2026 Feb 05. pii: S2666-979X(26)00003-0. [Epub ahead of print] 101141
    MultiSP deciphers tissue structure and multicellular communication from spatial multi-omics data.
    Chenfeng Mo, Xiufen Zou, Suoqin Jin.
      Recent breakthroughs in spatial multi-omics enable simultaneous profiling of different modalities while preserving tissue architecture, providing unprecedented opportunities to explore tissue complexity. However, due to the sparse and noisy nature of the data, interpreting these complex tissue structures and cellular communication remains challenging. We present MultiSP, a deep learning framework that enhances data representation through efficient spatial and feature similarity fusion, modality-specific probabilistic generative modeling, and cross-modality adversarial learning. Applied to various spatial multi-omics datasets, it outperforms existing methods in capturing biologically interpretable spatial domains. MultiSP also denoises spatial data, uncovers modality-specific spatial variations, and reveals gene regulation mechanisms. In the tumor microenvironment, it unravels fine-resolution cellular distribution maps, such as spatially neighboring macrophage-enriched sub-regions with distinct prognosis outcomes. Additionally, MultiSP facilitates the inference of spatially multimodal cell-cell communication. Together, MultiSP serves as a powerful framework for uncovering spatially multimodal heterogeneity and communication by integrating complementary information from multiple modalities.
    Keywords:  cell-cell communication; data denoising; data integration; deep learning; multimodal heterogeneity; spatial domain; spatial multi-omics; tissue organization
    DOI:  https://doi.org/10.1016/j.xgen.2026.101141
  11. FEMS Microbes. 2026 ;7 xtag002
    The role of Fusobacterium nucleatum in the tumour microenvironment and carcinogenesis of oral and colonic malignancies.
    Elisabetha Larionova, Gary P Moran.
      The intra-tumoural microbiome is an increasing area of research with potential benefits in cancer diagnostics and treatment development. Numerous studies have implicated Fusobacterium nucleatum, a member of the oral microbiota, in the development, immune evasion, and dissemination of oral and colorectal tumours. Although F. nucleatum is yet to be classified as a cause or consequence of cancer, reports indicate the microorganism's involvement in DNA damage, pathologic glucose uptake, and cellular proliferation. This accumulation of genetic instability is consistent with the multistep nature of malignant neoplasm progression. Virulence factors of F. nucleatum were shown to maintain an unresolved inflammatory state and impair the normal function of immune cells. The accompanying pro-inflammatory conditions facilitate vasculature remodelling, expediting tumour expansion, through a range of mechanisms. Pro-metastatic epithelial-to-mesenchymal transition and changes in gene expression have been observed in cancer cells upon F. nucleatum infection, suggesting an association with poorer prognosis. As a frequently encountered microorganism in the oral and colorectal intra-tumoural microbiome, F. nucleatum represents an intriguing, yet cautious research prospect with opportunities for novel prevention and therapeutic strategies. The objective of this work is to review the relevant evidence, taking into account the complexity of the tumour microenvironment.
    Keywords:  colorectal cancer; dysplasia; fusobacterium nucleatum; microbiota; oral cancer; tumour microenvironment
    DOI:  https://doi.org/10.1093/femsmc/xtag002
  12. Nature. 2026 Feb 04.
    Atlas-guided discovery of transcription factors for T cell programming.
    H Kay Chung, Cong Liu, Anamika Battu, Alexander N Jambor, Brandon M Pratt, Fucong Xie, Brian P Riesenberg, Eduardo Casillas, Ming Sun, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J Brown, Matthew Smith, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Z Audrey Wang, Jun Wang, Bryan Mcdonald, Peixiang He, Qiyuan Yang, Timothy Chen, Siva Karthik Varanasi, Michael LaPorte, Thomas H Mann, Dan Chen, Filipe Hoffmann, Josephine Ho, Jennifer Modliszewski, April Williams, Yusha Liu, Zhen Wang, Jieyuan Liu, Yiming Gao, Zhiting Hu, Ukrae H Cho, Longwei Liu, Yingxiao Wang, Diana C Hargreaves, Gianpietro Dotti, Barbara Savoldo, Jessica E Thaxton, J Justin Milner, Susan M Kaech, Wei Wang.
      CD8+ T cells differentiate into diverse states that shape immune outcomes in cancer and chronic infection1-4. To define systematically the transcription factors (TFs) driving these states, we built a comprehensive atlas integrating transcriptional and epigenetic data across nine CD8+ T cell states and inferred TF activity profiles. Our analysis catalogued TF activity fingerprints, uncovering regulatory mechanisms governing selective cell state differentiation. Leveraging this platform, we focused on two transcriptionally similar but functionally opposing states that are critical in tumour and viral contexts: terminally exhausted T (TEXterm) cells, which are dysfunctional5-8, and tissue-resident memory T (TRM) cells, which are protective9-13. Global TF community analysis revealed distinct biological pathways and TF-driven networks underlying protective versus dysfunctional states. Through in vivo CRISPR screening integrated with single-cell RNA sequencing (in vivo Perturb-seq) we delineated several TFs that selectively govern TEXterm cell differentiation. We also identified HIC1 and GFI1 as shared regulators of TEXterm and TRM cell differentiation and KLF6 as a unique regulator of TRM cells. We discovered new TEXterm-selective TFs, including ZSCAN20 and JDP2, with no previous known function in T cells. Targeted deletion of these TFs enhanced tumour control and synergized with immune checkpoint blockade but did not interfere with TRM cell formation. Consistently, their depletion in human T cells reduces the expression of inhibitory receptors and improves effector function. By decoupling exhaustion TEX-selective from protective TRM cell programmes, our platform enables more precise engineering of T cell states, accelerating the rational design of more effective cellular immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-025-09989-7
  13. Cancer Cell. 2026 Jan 29. pii: S1535-6108(26)00010-3. [Epub ahead of print]
    Emerging landscape of KRAS inhibitors in cancer treatment.
    Jakob M Riedl, Hiroyuki Matsubara, Reid McNeil, Parasvi S Patel, Ferran Fece de la Cruz, Doga C Gulhan, Ryan B Corcoran.
      Alterations in KRAS, NRAS, and HRAS occur in roughly 20% of patients with cancer, making RAS one of the most intensively studied oncogenic targets. The discovery of mutant-selective KRASG12C inhibitors has provided a proof-of-concept for RAS-directed therapies, heralding a new era in the treatment of RAS-driven cancers. Yet, the efficacy of first-generation KRASG12C inhibitors is limited by the rapid emergence of resistance. Novel classes of (K)RAS inhibitors with distinct mechanisms of action and broader target coverage hold promise to overcome resistance and extend the benefits of RAS-targeted therapies to a wider patient population. In this review, we summarize clinical evidence for KRASG12C inhibitors across tumor types and delineate key mechanisms of resistance. We further discuss the rapidly evolving landscape of next-generation (K)RAS inhibitors, with particular emphasis on their target selectivity, mechanisms of action, preliminary clinical efficacy, and the therapeutic opportunities and challenges inherent to each class.
    Keywords:  KRAS; KRAS G12C; KRAS inhibitor; colorectal cancer; drug resistance; non-small cell lung cancer; pancreatic cancer
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.001
  14. Expert Rev Gastroenterol Hepatol. 2026 Feb 04.
    Addressing current limitations of colonoscopy for colorectal cancer screening.
    Aastha Bharwad, Eric Yoon, Brooks D Cash.
       INTRODUCTION: Colonoscopy is widely accepted as the gold standard modality for colorectal cancer (CRC) screening and polyp surveillance. Colonoscopy has been shown to decrease the incidence and mortality of CRC and is the ground truth test to which new and alternative CRC screening modalities is compared. In the U.S. more than 15 million colonoscopies are performed yearly for CRC screening and the procedure is accepted as safe and effective. However, there are important limitations of colonoscopy for CRC screening that remain unresolved and continue to limit the maximal usefulness of this procedure.
    AREAS COVERED: This article will highlight some of the recognized limitations of colonoscopy for CRC screening including high costs, access and compliance barriers, preparation difficulties, complications, and performance variability.
    EXPERT OPINION: Colonoscopy is the gold-standard test for CRC screening but is subject to significant limitations. There have been important efforts directed toward mitigating the limitations of colonoscopy for CRC screening and these efforts have the potential to expand and enhance the use of colonoscopy as a CRC screening test in the future.
    Keywords:  Colon cancer screening; colonoscopy; complications; endoscopy; limitations
    DOI:  https://doi.org/10.1080/17474124.2026.2628015
  15. Cancer Discov. 2026 Feb 06. 16(2): 201-203
    Plasticity as Resistance: KRAS Inhibition Reveals WNT Adaptation in Metastatic Colorectal Cancer.
    George Eng, Omer H Yilmaz.
      Centonze and colleagues demonstrate that KRASG12D inhibition in metastatic colorectal cancer triggers rapid transcriptional reprogramming from a metastasis-associated EMP1+ state to a WNT-driven LGR5+ stem cell-like state, a plastic adaptation captured through real-time live cell imaging, revealing cell state conversion as a mechanism of therapeutic resistance that can be exploited through combinatorial targeting. See related article by Centonze et al., p. 320.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2147
  16. Cancer Commun (Lond). 2026 ;46 0002
    The Spatiotemporal Heterogeneity of Tumor-Associated Stromal Cells: Reprogramming Plasticity to Unlock Precision Cancer Immunotherapy.
    Yingying Lv, Tingfei Duan, Jinling Song, Shutong Liu, Zhaokai Zhou, Yuhao Ba, Siyuan Weng, Anning Zuo, Hui Xu, Peng Luo, Quan Cheng, Chuhan Zhang, Jingyuan Ning, Yukang Chen, Yuyuan Zhang, Zaoqu Liu, Xinwei Han.
      Tumor-associated stromal cells (TASCs) are key architects of the tumor microenvironment (TME), playing a vital role in tumor development, metastasis, and therapeutic response. Their spatiotemporal heterogeneity, characterized by dynamic phenotypic plasticity, diverse cellular subtypes, and distinct spatial distributions, offers profound insights into tumor behavior and paves the way for innovative therapy development. In particular, stromal-immune interactions reveal the powerful capacity of TASCs to shape the immune landscape, highlighting their potential as targets in immunotherapy. Despite growing evidence in functional diversity, precise mechanisms underlying the temporal evolution and spatial organization of TASCs remain elusive, impeding clinical translation. This review delved into the molecular signatures and functional states of TASCs, emphasizing their roles in tumor dynamics and therapeutic resistance. We also discussed innovative strategies targeting the plasticity of TASCs to reverse immune evasion and potentiate immune-mediated tumor eradication. Future studies should prioritize identifying spatially resolved and mechanically defined biomarkers with multi-omics and machine learning approaches, enabling a comprehensive understanding of TASCs to bridge the gap from bench to bedside.
    DOI:  https://doi.org/10.34133/cancomm.0002
  17. Nature. 2026 Feb 03.
    More than one-third of cancer cases are preventable, massive study finds.
    Gemma Conroy.
      
    Keywords:  Cancer; Epidemiology; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-00333-1
  18. Cancer Cell. 2026 Jan 29. pii: S1535-6108(26)00042-5. [Epub ahead of print]
    Lymph node colonization induces tissue remodeling via immunosuppressive fibroblast-myeloid cell niches supporting metastatic tolerance.
    Maximilian Haist, Marc-A Baertsch, Nathan E Reticker-Flynn, Guolan Lu, Tim N Kempchen, Pauline Chu, Gustavo Vazquez, Han Chen, John B Sunwoo, Weiruo Zhang, Eyiwunmi Laseinde, Bonny Adami, Stefanie Zimmer, Justus Kaufman, Quynh Thu Le, Andrew J Gentles, Christina S Kong, Sylvia K Plevritis, Yury Goltsev, John W Hickey, Garry P Nolan.
      Lymph node (LN) colonization in cancer is linked to poor prognosis. Evidence suggests that LN colonization induces systemic immunosuppression, facilitating distant metastasis. We investigated LN-mediated immunosuppression in patients with head-and-neck cancer using spatial proteomics, spatial transcriptomics, and an in vivo model of melanoma LN metastasis. Both primary tumors and paired LNs of nodal-positive patients exhibit enhanced interferon-γ signaling and an enrichment of immunosuppressive myeloid cells and cancer-associated fibroblasts (CAFs). The spatial intersection of these myeloid-CAF-enriched niches with perifollicular T cell zones and LN follicles is linked to enhanced T cell dysfunction and Treg activation therein, thereby driving architectural LN remodeling. These immune suppressive changes extend to adjacent non-tumor-involved LN regions and nearby tumor-free LNs, but were not detected in LNs of non-cancer patients, reflecting a systemic effect that compromises anti-tumor immunity beyond the tumor-involved LN. Hence, our findings establish LN colonization as an active driver of systemic immunosuppression, facilitating metastatic progression.
    Keywords:  cancer-associated fibroblasts; head-and-neck cancer; immunomodulation; lymph nodes; metastasis; multiplex imaging; spatial context; spatial transcriptomics; tumor immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.01.003
  19. Methods Cell Biol. 2026 ;pii: S0091-679X(25)00201-8. [Epub ahead of print]201 195-218
    Patient-derived models of tumor-immune cell interactions.
    Niloofar Nemati, Nina Boeck, Zlatko Trajanoski.
      Novel therapeutic approaches highlight the need for advanced ex vivo cell culture models that more closely resemble the physiological and genetic properties of the primary tumor. Patient-derived models could serve as an attractive strategy to investigate the crosstalk between cancer cells and its microenvironment and to test potential therapeutic targets, paving the way for precision oncology. In this chapter, we provide a detailed step-by-step protocol for enabling a direct co-culture system of patient-derived colorectal cancer (CRC) organoids with autologous tumor-infiltrating lymphocytes (TILs). The present protocol provides a methodology to gain direct access to the apical side of the epithelial cells forming the organoids. This method can be used to investigate patient-specific cell-to-cell interactions, T cell functionality and efficacy and provides a robust platform to validate potential immunogenic neoantigens.
    Keywords:  Co-culture; Ex vivo cell culture models; Immunotherapy; Organoids; Precision oncology; Tumor-immune cell interactions; Tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/bs.mcb.2025.10.001
  20. Phys Life Rev. 2026 Jan 29. pii: S1571-0645(26)00009-6. [Epub ahead of print]56 239-257
    Biophysical approaches to cancer diagnostics: Collagen biomarkers in colorectal cancer.
    Shimul Biswas, Krishna Kishore Mahato.
      Collagen remodeling in the extracellular matrix drives alterations in the physical, mechanical, and optical properties of tissues, representing a fundamental biophysical hallmark of colorectal cancer (CRC) progression. These changes, reflected in variations in collagen composition, molecular orientation, and cross-linking density, transform tissue stiffness, elasticity, and anisotropy, directly influencing cancer cell behavior and mechanotransduction. Understanding these structural and physical transitions requires analytical methods capable of probing the molecular origins of biomechanical alteration in situ. Spectroscopic and optical methodologies provide high-resolution, label-free detection of the vibrational, optical, and mechanical alteration associated with collagen remodeling. These techniques capture the shifts in molecular vibrational modes, nonlinear optical responses, and scattering anisotropy that arise from collagen fibril alignment, structural disorder, and cross-link formation, thereby connecting molecular architecture to measurable macroscale biomechanics. The integration of multimodal spectroscopy and incorporation of machine learning algorithms further enhance diagnostic performance by resolving complex tissue heterogeneity and improving tumor margin detection. Overall, this review demonstrates how spectroscopic techniques can be applied in the biomedical field for cancer detection by analyzing collagen remodeling and structural alterations.
    Keywords:  Biomarker; Cancer; Collagen; Colorectal; Diagnosis; Spectroscopy
    DOI:  https://doi.org/10.1016/j.plrev.2026.01.009
  21. Cancer Discov. 2026 Feb 04.
    TISSUE-SPECIFIC SPATIAL REGULATION OF INNATE IMMUNE CHECKPOINTS IN CANCER.
    Ana Stojanovic, Sebastiano Giorgetta, David Vonhören, Eva I Krieghoff-Henning, Michael Platten, Sonja Loges, Sonia Tugues, Adelheid Cerwenka.
      Natural killer (NK) and innate lymphoid cells (ILCs) regulate tissue homeostasis and immune responses, by acting as early sensors of cellular stress and tissue dysfunction. Their functions are tightly controlled by regulatory circuits, often referred to as checkpoints, and are profoundly shaped by local environments. In cancer, tissue perturbations cause immune cell recruitment, spatial re-distribution, and accordant functional adaptations. Here, we discuss how tissue-specific cues regulate NK/ILC functions in cancer, and how local regulatory circuits shape their cellular states and effector programs. We address how targeting innate checkpoints could aid existing, and inform novel strategies for treating solid malignancies.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-2112
  22. J Mol Biol. 2026 Jan 30. pii: S0022-2836(26)00043-4. [Epub ahead of print] 169670
    Rising Star: Single cell omics technologies: when whole omics analysis meets single cell resolution.
    Fuchou Tang.
      I got my PhD degree under the supervision of Prof. Kegang Shang in 2003. And I did my postdoc research in Azim Surani's lab. Then I set up my own lab in Biomedical Pioneering Innovation Center at Peking University in 2010. My research has focused on developing single-cell omics sequencing technologies and employing these powerful tools to dissect the gene regulation networks in human germline cell development under both physiological and pathological conditions. My lab systematically developed a serial of single-cell omics sequencing technologies, including the first single-cell DNA methylome sequencing technology in 2013, which was considered to pioneer the single-cell epigenome field. In recent years, my lab has focused on developing single-cell omics long-read sequencing technologies based on single-molecule sequencing platforms, which can reveal critical features of the repetitive elements. The repetitive elements are considered as 'dark matter', which account for over half of our genome and play important roles for both normal development and numerous diseases. The research in my lab revealed critical features of the epigenetic reprogramming of human germline cells, deepening our understanding of these cells which are fundamental to the transgenerational immortality of the human species.
    Keywords:  DNA methylation; Single-cell sequencing; epigenetic reprogramming; epigenome; genome; human germline development; long-read sequencing; mammalian embryonic development; next generation sequencing; repetitive element; single-molecule sequencing; transcriptome
    DOI:  https://doi.org/10.1016/j.jmb.2026.169670
  23. Cell. 2026 Feb 05. pii: S0092-8674(25)01438-2. [Epub ahead of print]189(3): 706-724
    Shifting paradigms in tissue stem cell biology: Insights from the intestine.
    Hans Clevers.
      The small intestinal epithelium represents the most rapidly self-renewing adult mammalian tissue, with a turnover time of 1-2 weeks. It contains ∼12 easily recognizable cell types with a wide diversity of functions, including nutrient absorption, mucus production, antimicrobial defense, and the regulation of metabolism by incretins like Glp1. The simple and repetitive crypt-villus architecture allows for easily interpretable experimentation in transgenic mice in vivo, while the human stem cell hierarchy is experimentally accessible in epithelial organoids in vitro. This review aims to comprehensively describe the design, the cellular constituents, and the molecular regulation of crypt-villus epithelial self-renewal. More generally, it highlights deviations from commonly held views on tissue stem cell biology: gut stem cells divide continually and symmetrically. They can be expanded indefinitely in vitro, while the plasticity of daughter cells can recreate stem cells during regeneration.
    DOI:  https://doi.org/10.1016/j.cell.2025.12.025
  24. ESMO Gastrointest Oncol. 2025 Mar;7 100136
    Re-evaluating population-level screening recommendations to address increasing early-onset colorectal cancer rates in Australia: a modelling study.
    Cancer Council Australia Colorectal Cancer Screening Working Party
       Background: The National Bowel Cancer Screening Program (NBCSP) sends free immunochemical faecal occult blood tests (iFOBTs) to eligible Australians aged 50-74 every 2 years. Rising early-onset colorectal cancer (CRC) rates in people under 50 have raised questions around optimising the NBCSP, contributing to the rationale for updating Australian CRC screening guidelines. To support this, alternative screening age ranges and approaches were evaluated.
    Methods: A microsimulation model was used to estimate the impact of 2-yearly iFOBT screening starting at age 40, 45 or 50 and/or stopping at 74, 79, or 84 in cohorts with rising incidence rates. Yearly iFOBT screening and 5-yearly stool biomarker testing were also analysed.
    Results: Lowering screening start ages to 45 or 40 could reduce CRC mortality rates by 5% and 10%, respectively, while extending stop ages to 79 or 85 could reduce CRC mortality rates by 3% and 5%, respectively. Lowering the start age would be more cost-effective and have a more favourable balance of benefits to harms versus raising the stop age.
    Conclusion: As early-onset CRC rates increase, lowering the screening start age could reduce CRC burden while remaining cost-effective and limiting harms. Based on these findings and implementation considerations, the Cancer Council Australia Colorectal Cancer Screening Working Party determined that 2-yearly iFOBT screening from age 45 to 74 was the most favourable. These analyses supported the 2023 Clinical practice guidelines for the prevention, early detection and management of colorectal cancer: Population Screening, which led to the NBCSP including people aged 45-49 on an opt-in basis from July 2024.
    Keywords:  colorectal cancer; epidemiology; health economics; modelling; prevention and early detection; screening
    DOI:  https://doi.org/10.1016/j.esmogo.2025.100136
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒27 at 12:43.