bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–12–07
thirty-one papers selected by
Xiao Qin, University of Oxford
  1. A guide to transcriptomic deconvolution in cancer.
  2. Decay of driver mutations shapes the landscape of intestinal transformation.
  3. A unified genetic perturbation language for human cellular programming.
  4. Tumor-initiating stem cells engineer immunity.
  5. CancerTrace: Multi-stage single-cell analysis of networked cancer evolution for driver and modulator gene identification.
  6. Protocol to track single-cell-derived clones using DNA barcoding combined with single-cell RNA sequencing.
  7. Bioengineering mini-colons for ex vivo colorectal cancer research.
  8. Dual role of Oct4 and Sox2 in controlling the developmental capacity and timing of tissue morphogenesis in the embryonic lineage.
  9. Editorial: Histone modifications in cancer.
  10. Expansion omics: from expansion microscopy to spatial omics.
  11. Deciphering cell-fate trajectories using spatiotemporal single-cell transcriptomic data.
  12. Colorectal cancer stem cells crosstalk in tumor immune microenvironment and targeted therapeutic strategies.
  13. SwitchTFI: identifying transcription factors driving cell differentiation.
  14. Multimodal foundation transformer models for multiscale genomics.
  15. Lineage tracing technology for decoding cell evolution in pathophysiology: a bibliometric analysis.
  16. Reconstructing Waddington's landscape from data.
  17. Order in which cancer-driving mutations occur affects the chance of tumour development.
  18. Beyond Multilevel Selection in Cancer: Rethinking Metastasis Through Selection for Function.
  19. Ancient DNA insights into diverse pathogens and their hosts.
  20. Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche.
  21. AI is saving time and money in research - but at what cost?
  22. Sex differences in gene regulation and its impact on cancer incidence.
  23. The landscape of regulated cell death: It's all downhill from here.
  24. RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer.
  25. Deciphering precursor cell dynamics in esophageal preneoplasia via genetic barcoding and single-cell transcriptomics.
  26. Cancer-associated fibroblasts: Recent advances and therapeutic implications.
  27. Modeling gut inflammation using intestinal organoids: Advances, challenges, and future perspectives.
  28. Emerging risk factors and the role of gut microbiota in immunomodulation and therapeutic implications in colorectal cancer.
  29. Cellular characteristics of the immune microenvironment of colorectal cancer and progress in immunotherapy research.
  30. Non-invasive colorectal cancer screening methods: focusing on diagnostic genetic and epigenetic markers.
  31. Decrypting cellular engagement and recruitment from spatially resolved transcriptomics.
  1. Nat Rev Cancer. 2025 Dec 02.
    A guide to transcriptomic deconvolution in cancer.
    Yaoyi Dai, Shuai Guo, Yidan Pan, Carla Castignani, Matthew D Montierth, Peter Van Loo, Wenyi Wang.
      Cancer tissues are heterogeneous mixtures of tumour, stromal and immune cells, where each component comprises multiple distinct cell types and/or states. Mapping this heterogeneity and understanding the unique contributions of each cell type to the tumour transcriptome is crucial for advancing cancer biology, yet high-throughput expression profiles from tumour tissues only represent combined signals from all cellular sources. Computational deconvolution of these mixed signals has emerged as a powerful approach to dissect both cellular composition and cell-type-specific expression patterns. Here, we provide a comprehensive guide to transcriptomic deconvolution, specifically tailored for cancer researchers, presenting a systematic framework for selecting and applying deconvolution methods, considering the unique complexities of tumour tissues, data availability and method assumptions. We detail 43 deconvolution methods and outline how different approaches serve distinctive applications in cancer research: from understanding tumour-immune surveillance to identifying cancer subtypes, discovering prognostic biomarkers and characterizing spatial tumour architecture. By examining the capabilities and limitations of these methods, we highlight emerging trends and future directions, particularly in addressing tumour cell plasticity and dynamic cell states.
    DOI:  https://doi.org/10.1038/s41568-025-00886-9
  2. Nature. 2025 Dec 03.
    Decay of driver mutations shapes the landscape of intestinal transformation.
    Filipe C Lourenço, Iannish D Sadien, Kim Wong, Sam Adler, Ashley Sawle, Leonor Schubert Santana, Lee Hazelwood, Giada Giavara, Anna M Nicholson, Matthew D Eldridge, Noori Maka, Gerard Lynch, Stephen T McSorley, Joanne Edwards, Richard Kemp, David J Adams, Douglas J Winton.
      Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of the APC tumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins1-4. Here, by mediating transformation on different mouse backgrounds containing mutations in Kras or other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations in Apc and Ctnnb1 that are otherwise lost due to negative selection. These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development.
    DOI:  https://doi.org/10.1038/s41586-025-09762-w
  3. bioRxiv. 2025 Nov 20. pii: 2025.11.20.689421. [Epub ahead of print]
    A unified genetic perturbation language for human cellular programming.
    Austin Hartman, Oliver Takacsi-Nagy, Courtney Kernick, Nicole E Theberath, Johnathan Lu, Lujing Wu, Michelle Mantilla, Siddhesh Mittra, Alison McClellan, Nicole Johnson, Lina Mohamad, Lesly Castillo-Colin, Farzad Hoque, Alexander Eapen, Andy Chen, Laura M Moser, Trini Rogando, Anabella Hernandez, Katherine Santostefano, Ansuman T Satpathy, Theodore L Roth.
      Evolution simultaneously and combinatorially explores complex genetic changes across perturbation classes, including gene knockouts, knockdowns, overexpression, and the creation of new genes from existing domains. Separate technologies are capable of genetic perturbations at scale in human cells, but these methods are largely mutually incompatible. Here we present CRISPR-All, a unified genetic perturbation language for programming of any major type of genetic perturbation simultaneously, in any combination, at genome scale, in primary human cells. This is enabled by a standardized molecular architecture for each major perturbation class, development of a functional syntax for combining arbitrary numbers of elements across classes, and linkage to unique single cell compatible barcodes. To facilitate use, CRISPR-All converts high level descriptions of desired complex genetic changes into a single DNA sequence that can rewire genomic programs within a cell. Using the CRISPR-All language allowed for head-to-head functional comparisons across perturbation types in a comprehensive analysis of all previously identified genetic enhancements of human CAR-T cells. Combining CRISPR-All programs with single cell RNA sequencing revealed a greater diversity of phenotypic states, including improved functional performance, only accessible through distinct perturbation classes. Finally, CRISPR-All combinatorial genome scale screening of up to four distinct perturbations simultaneously revealed additive functional improvements in human T cells accessible only through iterative multiplexing of modifications across perturbation classes. CRISPR-All enables exploration of a combinatorial genetic perturbation space, which may be impactful for biological and clinical applications.
    DOI:  https://doi.org/10.1101/2025.11.20.689421
  4. Cancer Cell. 2025 Dec 04. pii: S1535-6108(25)00453-2. [Epub ahead of print]
    Tumor-initiating stem cells engineer immunity.
    Zhe Yang, Linheng Li.
      Immunotherapy reshapes the interaction between the tumor microenvironment and cancer stem cells. In this issue of Cancer Cell, Guo et al. revealed that SOX2High tumor-initiating stem cells reprogram neutrophils that block interferon-induced reprogramming after immunotherapy, maintaining their pro-tumor phenotype at the tumor-stroma interface.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.012
  5. Comput Struct Biotechnol J. 2025 ;27 5061-5077
    CancerTrace: Multi-stage single-cell analysis of networked cancer evolution for driver and modulator gene identification.
    Komlan Atitey, Caitlin E Hughes, Joseph C Fusco.
      Identifying patient-specific cancer driver genes and their upstream modulators remains challenging due to temporal heterogeneity and the lack of matched multi-omics data. Existing methods often rely on large cohorts with DNA or perturbation assays, treat gene expression as static correlation rather than directed influence, or recover broad regulatory modules without resolving causal, time-resolved driver-modulator relationships. To overcome these limitations, we introduce CancerTrace, a time-aware computational framework that operates directly on single-cell RNA sequencing (scRNA-seq) data to recover dynamic, patient-specific regulatory mechanisms. CancerTrace integrates Transfer Entropy and sparse conditional structure within a variational Bayesian model to (i) isolate the malignant compartment, (ii) reconstruct stage-resolved expression dynamics, and (iii) map directed influence from modulators to drivers. It yields ranked drivers, driver-centered influence networks, and in-silico perturbation readouts without requiring matched DNA or external perturbations. Applied to nine longitudinal scRNA-seq libraries from three lung adenocarcinoma (LUAD) patients, CancerTrace identified an EpCAM-anchored epithelial compartment and recovered both canonical and novel drivers. Over half of the top epithelial drivers corresponded to known oncogenes or tumor suppressors, while VPS37D and ATP11 AUN emerged as new candidates. Driver coefficients for TP53INP1, CA12, and CCNL1 aligned with known biology, and epithelial drivers exerted measurable influence on NK cells, consistent with their stage-wise decline. By leveraging temporal single-cell structure, CancerTrace transcends the static and cohort-dependent limitations of existing tools, inferring causal, time-directed driver-modulator relationships that advance mechanistic understanding and precision oncology.
    Keywords:  Cancer driver genes; Gene regulatory networks; Lung adenocarcinoma; Non-driver regulators; Single-cell RNA-seq; Variational Bayesian inference
    DOI:  https://doi.org/10.1016/j.csbj.2025.11.014
  6. STAR Protoc. 2025 Nov 27. pii: S2666-1667(25)00635-5. [Epub ahead of print]6(4): 104229
    Protocol to track single-cell-derived clones using DNA barcoding combined with single-cell RNA sequencing.
    Hee Jin Shin, Sahil Sharma, Sarah Kronheim, May Cheung, Long V Nguyen.
      Clonal fitness and plasticity drive tumor heterogeneity contributing to disease progression and treatment resistance. Here, we provide a protocol to track the clonal outputs from uniquely marked cells. We describe steps for constructing and validating lentiviral DNA barcode libraries. We then detail procedures for single-cell RNA sequencing. This approach links clonal growth activity with transcriptomic profiles and enables permanent cellular labeling to track clonal dynamics in various model systems, which can provide insight into molecular processes underlying clone function. For complete details on the use and execution of this protocol, please refer to Nguyen et al.1.
    Keywords:  Cancer; Cell Biology; RNA-seq; Sequence analysis; Sequencing; Single Cell
    DOI:  https://doi.org/10.1016/j.xpro.2025.104229
  7. Nat Protoc. 2025 Dec 03.
    Bioengineering mini-colons for ex vivo colorectal cancer research.
    L Francisco Lorenzo-Martín, Tania Hübscher, Jakob Langer, Mikhail Nikolaev, Matthias P Lutolf.
      Tumor initiation remains one of the least understood events in cancer biology, largely due to the challenge of dissecting the intricacy of the tumorigenic process in laboratory settings. The insufficient biological complexity of conventional in vitro systems makes animal models the primary experimental approach to study tumorigenesis. Despite providing valuable insights, these in vivo models function as experimental black boxes with limited spatiotemporal resolution of cellular dynamics during oncogenesis. In addition, their use raises ethical concerns, further underscoring the need for alternative ex vivo systems. Here we provide a detailed protocol to integrate state-of-the-art microfabrication, tissue engineering and optogenetic approaches to generate topobiologically complex miniature colons ('mini-colons') capable of undergoing tumorigenesis in vitro. We describe the key methodology for the generation of blue light-inducible oncogenic cells, the establishment of hydrogel-based mini-colon scaffolds within microfluidic devices, the development of mini-colons and the induction of spatiotemporally controlled tumorigenesis. This protocol enables the formation and long-term culture of complex cancerous tissues that capture in vivo-like tumoral biology while offering real-time and single-cell resolution analyses. It can be implemented in 4-6 weeks by researchers with prior experience in 3D cell culture techniques. We anticipate that these methodological guidelines will have a broad impact on the cancer research community by opening new avenues for tumorigenesis studies.
    DOI:  https://doi.org/10.1038/s41596-025-01292-z
  8. Dev Cell. 2025 Dec 02. pii: S1534-5807(25)00695-1. [Epub ahead of print]
    Dual role of Oct4 and Sox2 in controlling the developmental capacity and timing of tissue morphogenesis in the embryonic lineage.
    Deepthi Chandramohan, Rongge Yan, Kai Kruse, Heike Brinkmann, Hyun-Woo Jeong, Yanlin Hou, Kenjiro Adachi, Hans R Schöler, Ivan Bedzhov.
      The fundamental processes of cell fate specification, differentiation, and morphogenesis must be finely synchronized to enable proper developmental progression, yet the molecular factors coordinating these processes are not well understood. A key driver of embryonic morphogenesis is the establishment of epithelial polarity, which organizes and structures the early cell layers. Here, we investigated factors controlling the epithelialization in epiblast cells and implemented sequential loss-of-function approaches in mouse embryos to define the timing of developmental significance. We found that the expression wave of the core pluripotency factors Oct4 and Sox2 following the 8-cell stage plays a critical role in this process. In this context, one of the key shared functions of these factors is to prevent premature activation of the epithelial program until the completion of the second lineage segregation. Thus, Oct4 and Sox2 simultaneously govern developmental capacity and regulate the developmental timing of tissue morphogenesis of the embryonic lineage.
    Keywords:  ICM; Oct4; Sox2; blastocyst; core pluripotency factors; embryo; epiblast; epithelial polarity; morphogenesis; mouse
    DOI:  https://doi.org/10.1016/j.devcel.2025.11.003
  9. Front Pharmacol. 2025 ;16 1727417
    Editorial: Histone modifications in cancer.
    Jiaqian Luo, Sizhi P Gao.
      
    Keywords:  cancer biology; epigenetic therapies; epigenetics; histone modification; methylation; precision oncology; superenhancer; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fphar.2025.1727417
  10. Mol Syst Biol. 2025 Dec 01.
    Expansion omics: from expansion microscopy to spatial omics.
    Zhen Dong, Weirong Xiang, Wenhao Jiang, Tiannan Guo.
      Tissue expansion, originally developed for super-resolution imaging, has become a foundation for expansion omics (ExO), a growing field that uses physical tissue expansion to enable spatially resolved omics profiling. In this perspective, we explore how ExO integrates multi-omics through chemical anchoring strategies that ensure selective retention of diverse molecular species, together with improved spatial resolution from the subcellular resolution for profiling to the sub-nanometer scale for imaging, allowing precise detection of biomolecules and their link with biological function. These capabilities have empowered tissue expansion to be successfully applied across multiple spatial omics modalities, including epigenomics, transcriptomics, proteomics, and lipidomics, enabling high-resolution mapping of chromatin states, gene expression, protein localization, and lipid distributions. Moreover, ExO supports spatial multi-omics approaches that jointly capture and correlate multiple biomolecular dimensions within the same tissue context. However, challenges remain in expansion resolution, molecular retention, hydrogel adaptability, data scalability, and AI-driven analysis. As tissue expansion evolves, its integration of super-resolution imaging and spatial omics establishes it as a core technology for whole-slide, single-cell multi-omics and the development of the Artificial Intelligence Virtual Cell, advancing spatial biology and medicine.
    DOI:  https://doi.org/10.1038/s44320-025-00171-9
  11. NPJ Syst Biol Appl. 2025 Dec 04.
    Deciphering cell-fate trajectories using spatiotemporal single-cell transcriptomic data.
    Zhenyi Zhang, Zihan Wang, Yuhao Sun, Jiantao Shen, Qiangwei Peng, Tiejun Li, Peijie Zhou.
      Cellular processes evolve dynamically across time and space. Single-cell and spatial omics technologies have provided high-resolution snapshots of gene expression, greatly expanding the capability to characterize cellular states. This review summarizes recent modeling strategies for time-series and spatiotemporal transcriptomic data, emphasizing links between dynamical systems, generative modeling, and biological insight. These approaches illustrate how computational tools can deepen our understanding of the dynamic nature of single cells.
    DOI:  https://doi.org/10.1038/s41540-025-00624-9
  12. Front Immunol. 2025 ;16 1714954
    Colorectal cancer stem cells crosstalk in tumor immune microenvironment and targeted therapeutic strategies.
    Yuxuan Duan, Anshu Li, Daojia Miao, Diaoyi Tan, Keshan Wang, Jian Shi.
      Colorectal cancer (CRC) remains a formidable clinical challenge due to therapy resistance, metastasis, and relapse. Central to these processes are colorectal cancer stem cells (CCSCs), a dynamic subpopulation endowed with self-renewal capacity, plasticity, and heterogeneity. This review synthesizes recent advancements in understanding how CCSCs orchestrate tumor progression through intricate bidirectional crosstalk with the tumor immune microenvironment (TIME). We begin by elucidating the cellular origins of CCSCs, their profound intratumoral heterogeneity, and their remarkable phenotypic plasticity-driven by genetic, epigenetic, and metabolic reprogramming-which collectively serve as the root cause of therapeutic failure. A significant portion of our discussion is dedicated to deconstructing the immunosuppressive niche co-opted by CCSCs. We detail mechanisms of immune evasion and tolerance, highlighting how CCSCs modulate innate and adaptive immune cells-including NK cells, Tregs, dendritic cells, macrophages, neutrophils, and myeloid-derived suppressor cells-to foster an environment that supports stemness and suppresses cytotoxic attack. This reciprocal interaction forms a vicious cycle that perpetuates tumor survival and progression. Finally, we critically evaluate emerging therapeutic strategies that concurrently target CCSC-specific vulnerabilities and counteract immunosuppression. We explore the limitations of conventional chemotherapy and the promise of targeted therapies (e.g., Wnt inhibitors), immunotherapies (e.g., CAR-T, bispecific antibodies), and combination regimens designed to remodel the TIME and eradicate the CCSC reservoir. By integrating insights from single-cell omics and spatial biology, this review provides a comprehensive framework for overcoming therapy resistance and proposes novel precision medicine approaches for CRC.
    Keywords:  colorectal cancer; colorectal cancer stem cells; immunosuppression; immunotherapy; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1714954
  13. Genome Biol. 2025 Dec 02. 26(1): 410
    SwitchTFI: identifying transcription factors driving cell differentiation.
    Paul Martini, Anne Hartebrodt, Gustavo P de Almeida, Carl-Philipp Hackstein, Dietmar Zehn, David B Blumenthal.
      
    Keywords:  Cell differentiation; Gene regulatory networks; Single-cell gene expression data; Transcription factors
    DOI:  https://doi.org/10.1186/s13059-025-03876-0
  14. Nat Methods. 2025 Dec 01.
    Multimodal foundation transformer models for multiscale genomics.
    Sumeer Ahmad Khan, Xabier Martínez-de-Morentin, Abdel Rahman Alsabbagh, Alberto Maillo, Vincenzo Lagani, David Gomez-Cabrero, Robert Lehmann, Jesper Tegner.
      Transformer-based models are rapidly becoming foundational tools for analyzing and integrating multiscale biological data. This Perspective examines recent advances in transformer architectures, tracing their evolution from unimodal and augmented unimodal models to large-scale multimodal foundation models operating across genomic sequences, single-cell transcriptomics and spatial data. We categorize these models into three tiers and evaluate their capabilities for structural learning, representation transfer and tasks such as cell annotation, prediction and imputation. While discussing tokenization, interpretability and scalability challenges, we highlight emerging approaches that leverage masked modeling, contrastive learning and large language models. To support broader adoption, we provide practical guidance through code-based primers, using public datasets and open-source implementations. Finally, we propose designing a modular 'Super Transformer' architecture using cross-attention mechanisms to integrate heterogeneous modalities. This Perspective serves as a resource and roadmap for leveraging transformer models in multiscale, multimodal genomics.
    DOI:  https://doi.org/10.1038/s41592-025-02918-6
  15. Int J Surg. 2025 Nov 20.
    Lineage tracing technology for decoding cell evolution in pathophysiology: a bibliometric analysis.
    Lincheng Zhang, Xuan Wang, Shuang Wang, Yingxuan Ma, Yannan Cao, Xiangsong Zhang, Yiwei Lu, Shuyong Wang, Yunfang Wang.
      Lineage tracing technology has become a pivotal tool in life sciences. This article comprehensively reviews the current status, hotspots, and trends in this field. A total of 3252 relevant articles published from 1 January 1979, to 22 September 2024, were retrieved from the Web of Science Core Collection. We utilized VOSviewer for co-authorship networks, CiteSpace for keyword/reference analysis, Bibliometrix for bibliometric indicators and theme evolution, and Pajek for layout optimization. Research has been conducted in 70 countries/regions, involving 2434 institutions and 18 906 researchers, with the United States and China being the two most prolific countries in terms of publications. Key findings reveal a significant growth in publications over the past decade, reflecting the increasing utility of lineage tracing across disciplines such as developmental biology, regenerative medicine, and cancer research. In addition, the bibliometric analysis uncovered the trajectory of lineage tracing technology in terms of persistence, specificity, and spatial and temporal resolution of cell labeling methods. In the future, we should welcome the integration of spatial transcriptomics technologies to further improve the spatial and temporal resolution of lineage tracing technology. Taken together, this work identifies key research frontiers and bridges a significant gap in current literature by providing researchers and clinicians with a systematic knowledge framework for understanding the evolution and application of lineage tracing technologies. As the first bibliometric synthesis integrating quantitative mapping with technological evolution analysis, this study overcomes the limitations of narrative reviews through data-driven decision-making, algorithmic processing, standardized analytical tools, and multidimensional metric cross-validation.
    Keywords:  bibliometrics; cell fate; developmental biology; lineage tracing technology; regeneration
    DOI:  https://doi.org/10.1097/JS9.0000000000003916
  16. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2521762122
    Reconstructing Waddington's landscape from data.
    Dillon J Cislo, M Joaquina Delás, James Briscoe, Eric D Siggia.
      The development of a zygote into a functional organism requires that this single progenitor cell gives rise to numerous distinct cell types. Attempts to exhaustively tabulate the interactions within developmental signaling networks that coordinate these hierarchical cell fate transitions are difficult to interpret or fit to data. An alternative approach models the cellular decision-making process as a flow in an abstract landscape whose signal-dependent topography defines the possible developmental outcomes and the transitions between them. Prior applications of this formalism have built landscapes in low-dimensional spaces without explicit maps to gene expression. Here, we present a computational geometry framework for fitting dynamical landscapes directly to high-dimensional single-cell data. Our method models the time evolution of probability distributions in gene expression space, enabling landscape construction with minimal free parameters and precise characterization of dynamical features, including fixed points, unstable manifolds, and basins of attraction. We demonstrate the applicability of this framework to multicolor flow-cytometry and RNA-seq data. Applied to a stem cell system that models ventral neural tube patterning, we recover a family of morphogen-dependent landscapes whose valleys align with canonical neural progenitor types. Remarkably, simple linear interpolation between landscapes captures signaling dependence, and chaining landscapes together reveals irreversible behavior following transient morphogen exposure. Our method combines the interpretability of landscape models with a direct connection to data, providing a general framework for understanding and controlling developmental dynamics.
    Keywords:  Morse–Smale; Waddington landscape; dimensional reduction; transcription profiling
    DOI:  https://doi.org/10.1073/pnas.2521762122
  17. Nature. 2025 Dec 03.
    Order in which cancer-driving mutations occur affects the chance of tumour development.
      
    Keywords:  Cancer; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-03748-4
  18. Bioessays. 2025 Dec 03. e70094
    Beyond Multilevel Selection in Cancer: Rethinking Metastasis Through Selection for Function.
    Frédéric Thomas, Antoine M Dujon.
      Laplane et al. recently provided a valuable framework for understanding cancer evolution through multilevel selection (MLS), distinguishing between MLS1, where groups differ in persistence based on the traits of their constituent cells but do not reproduce or evolve group-level adaptations, and MLS2, where groups themselves reproduce and possess emergent fitness distinct from that of individual cells. However, as the authors themselves acknowledge, applying MLS2 to metastasis is challenging for several reasons. We argue that, rather than behaving as isolated evolutionary units, tumor sites function as components of a distributed system. This perspective suggests that metastasis may be better understood through the lens of selection for function, a framework that explains how traits contributing to system-level persistence can be maintained without requiring group-level reproduction. This approach complements MLS theory and helps account for the resilience of the metastatic system as a whole, namely, the persistence and coordination of multiple tumor sites functioning as a collective rather than as isolated tumors, beyond classical Darwinian models. It also aligns with the view that metastasis may reflect the reactivation of ancient cellular programs in a novel, nonreproductive context.
    DOI:  https://doi.org/10.1002/bies.70094
  19. Nat Rev Genet. 2026 Jan;27(1): 96-111
    Ancient DNA insights into diverse pathogens and their hosts.
    Kelly E Blevins, María C Ávila-Arcos, Verena J Schuenemann, Anne C Stone.
      Pathogen emergence and adaptation are constant, but the mechanisms underlying pathogen success as well as host susceptibility and resistance are often only observable in time series data. Ancient DNA research of pathogens and their hosts provides unique insights into past occurrences, including the changes that led to pathogen jumps between animals and humans, pandemic outbreaks, the timing of such events and the genetic, cultural and ecological factors that affect pathogen success and human survival and recovery. Recent technological improvements and the increasing number of ancient samples analysed have enabled the unprecedented investigation of pathogen evolution. Such studies are poised to benefit from the increased diversity of sequenced ancient pathogens, adoption of a broader framework that considers the entire ecosystem of host-pathogen interactions and growing collaboration with related fields.
    DOI:  https://doi.org/10.1038/s41576-025-00912-4
  20. Cancer Cell. 2025 Dec 04. pii: S1535-6108(25)00494-5. [Epub ahead of print]
    Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche.
    Weijie Guo, Jingyun Luan, Xuejie Huang, Daniel Leon, Sophie Gang, Benjamin Nicholson, Breanna Bertacchi, Diana Bolotin, Mark W Lingen, Alexander T Pearson, Evgeny Izumchenko, Ari J Rosenberg, Nishant Agrawal, Everett E Vokes, Siwakorn Punyawatthananukool, Shuh Narumiya, Matthias Gunzer, Iván Ballesteros, Andrés Hidalgo, Yuxuan Miao.
      The heterogeneous nature of tumor-associated neutrophils (TANs) has been recognized, but how different cell states of TANs emerge, evolve, distribute, and impact cancer immunotherapy efficacy remain elusive. Using single-cell RNA sequencing, spatial transcriptomics, and genetic manipulations, we show that anti-PDL1 + CD40 agonist immunotherapy can induce interferon responses in TANs, allowing them to regain anti-tumor activities in squamous cell carcinomas (SCCs). In contrast, TANs residing at the tumor-stroma interface can preserve their immune-suppressive state. Importantly, we identify a group of SOX2High tumor-initiating stem cells (tSCs) at the tumor-stroma interface that upregulate fatty acid desaturase 1 (Fads1) to produce arachidonic acid (AA). This tSC-specific pathway enhances the prostaglandin E2 (PGE2) signaling in TANs, which can disrupt the interferon response and prevent the interferon-induced anti-tumor functions in TANs. By fine-tuning the plasticity of neutrophils, tSCs shape neutrophil heterogeneity and sculpt a protective micro-niche to survive from immunotherapy and drive cancer relapse.
    Keywords:  Fads1; Sox2; arachidonic acid; cancer relapse; immunotherapy; interferon response; prostaglandin E2; squamous cell carcinoma; tumor-associated neutrophils; tumor-initiaiting stem cells
    DOI:  https://doi.org/10.1016/j.ccell.2025.11.001
  21. Nature. 2025 Dec 05.
    AI is saving time and money in research - but at what cost?
    Rachel Fieldhouse.
      
    Keywords:  Ethics; Machine learning; Technology
    DOI:  https://doi.org/10.1038/d41586-025-03936-2
  22. bioRxiv. 2025 Nov 22. pii: 2025.11.21.689715. [Epub ahead of print]
    Sex differences in gene regulation and its impact on cancer incidence.
    Camila M Lopes-Ramos, Rebekka Burkholz, Marouen Ben Guebila, Viola Fanfani, Enakshi Saha, Katherine H Shutta, Kimberly Glass, John Quackenbush, Dawn L DeMeo.
      Sex differences in the incidence rates of many cancer types are well-documented. While differences in lifestyle, environmental exposures, and hormone levels can influence disease risk and incidence, there is limited understanding of how cancer driver genes are differentially regulated between males and females in normal tissues, and how these differences may contribute to the observed sex differences in cancer epidemiology. We studied 8,279 gene regulatory networks across 29 non-cancerous tissues in the GTEx dataset, referred here as normal tissues. Using network centrality measures, we compared the networks between males and females, focusing on interactions between 644 transcription factors and 476 cancer genes (COSMIC Cancer Gene Census). Cancer genes were differentially targeted by transcription factors in males and females across normal tissues. We found an overrepresentation of sex-biased cancer genes on the X chromosome, particularly among genes escaping X chromosome inactivation, with higher regulatory targeting of tumor suppressor genes in females compared to males. Key signaling pathways, including WNT, NOTCH, and p53, showed differential transcriptional targeting by sex. We observed higher targeting of cancer-related pathways in females for tissues that have higher tumor incidence in females (breast, lung, and thyroid) and higher targeting in males for tissues with increased tumor incidence in males (stomach, colon, and liver). Sex-biased transcription factors that were consistently observed across multiple tissues are enriched for sex hormone response elements in their promoters. Our findings showed that normal tissues have sex-biased regulation of genes implicated in tumorigenesis, helping to explain the molecular basis of sex differences observed in cancer incidence rates and in identifying targets for cancer prevention in a sex-aware manner.
    DOI:  https://doi.org/10.1101/2025.11.21.689715
  23. Mol Cell. 2025 Dec 03. pii: S1097-2765(25)00909-8. [Epub ahead of print]
    The landscape of regulated cell death: It's all downhill from here.
    Andreas Aufschnaiter, Teak-Jung Oh, Andrew Oberst.
      Cells can die via any of several forms of regulated cell death (RCD), including apoptosis, pyroptosis, and necroptosis. We now appreciate that there is substantial crosstalk between them, allowing for a high degree of plasticity downstream of cell death triggers. Understanding this is essential to delineate roles of RCD in development, homeostasis, tumor biology, and immunity; however, this crosstalk can make the fate of individual cells difficult to visualize. Here, we present a conceptual framework that builds on Waddington's landscape model of lineage commitment. On the landscape of RCD, live cells begin atop a "mountain," from which they roll down via "valleys" representing different cell death programs, potentially being diverted or even raised back to the summit by regulators of these processes. While acknowledging that, like any conceptual framework, this visualization is imperfect, we hope it presents a succinct approach to understand the complexities and interconnections of cell death regulation.
    Keywords:  apoptosis; necroptosis; programmed cell death; pyroptosis; regulated cell death
    DOI:  https://doi.org/10.1016/j.molcel.2025.11.013
  24. Nat Cell Biol. 2025 Dec 01.
    RASH3D19 mediates RAS activation through a positive feedback loop in KRAS-mutant cancer.
    Warapen Treekitkarnmongkol, Hiroshi Katayama, Deivendran Sankaran, Mei-Chee Tai, Sanchita Rauth, Hanxiao Chen, Tristian Nguyen, Kieko Hara, Fredrik I Thege, Moorthy P Ponnusamy, Surinder K Batra, Huamin Wang, Ignacio I Wistuba, Thomas D Schmittgen, John V Heymach, Scott Kopetz, Tony Hu, Wantong Yao, Anirban Maitra, Subrata Sen.
      Therapeutic targeting of mutant KRAS pathways driving cancers is being actively investigated to identify feedback mechanisms responsible for the development of adaptive resistance to mutant KRAS inhibitors undergoing clinical trials. Here we report RASH3D19 as a mediator of RAS pathway activation through a positive feedback loop involving the KRAS-microRNA signalling axis. KRAS-induced miR-222 represses ETS1 expression and downstream transactivation of miR-301a leading to elevation of its target RASH3D19. RASH3D19 facilitates activation of RAS pathways by promoting dimerization and interaction of EGFR with the SOS2, GRB2, SHP2 and GAB1 complex. Genetic deletion of RASH3D19 in mutant KRAS-expressing cancer cells exhibits growth retardation in vitro, in vivo and sensitized pancreatic ductal adenocarcinoma and colorectal cancer cells, organoids and xenografts to mutant KRAS inhibitors, suppressing feedback reactivation of RAS pathways. Therapeutic targeting of RASH3D19 is expected to lead to tumour debulking and alleviating resistance to KRAS inhibitors in mutant KRAS-expressing cancers.
    DOI:  https://doi.org/10.1038/s41556-025-01816-5
  25. Proc Natl Acad Sci U S A. 2025 Dec 09. 122(49): e2509534122
    Deciphering precursor cell dynamics in esophageal preneoplasia via genetic barcoding and single-cell transcriptomics.
    Jinho Jang, Kyung-Pil Ko, Jie Zhang, Sohee Jun, Jae-Il Park.
      Although histologically normal, esophageal preneoplastic cells harbor early genetic alterations and likely exhibit lineage plasticity. However, their origins and trajectories remain unclear. To address this, we combined genetic barcoding with single-cell RNA sequencing to trace the lineage of esophageal preneoplastic cells. We identified a distinct progenitor-like cell population with high plasticity. Through a scoring system, these high-plasticity cells are mapped, revealing their contributions to proliferative and basal cell populations. This approach uncovers molecular markers, including Nfib and Qk, that define these precursor cells, validated by spatial transcriptomics and a Trp53 Cdkn2a Notch1 mouse model. These findings provide critical insights into early tumorigenesis, highlighting the potential of precursor cells as biomarkers for early detection and therapeutic targets of esophageal squamous cell cancer. By elucidating the cellular dynamics underlying esophageal preneoplasia, this research lays the foundation for strategies to prevent malignant progression, offering broader implications for improving cancer diagnostics and treatment approaches.
    Keywords:  cell lineage tracing; esophageal squamous cell cancer; genetic barcoding; preneoplasia; single-cell transcriptomics
    DOI:  https://doi.org/10.1073/pnas.2509534122
  26. Curr Opin Cell Biol. 2025 Dec 01. pii: S0955-0674(25)00139-5. [Epub ahead of print]98 102601
    Cancer-associated fibroblasts: Recent advances and therapeutic implications.
    Christina Paraskeva, Athanasia Stavropoulou, Vasiliki Koliaraki.
      The tumor microenvironment (TME) plays a crucial role in cancer initiation, progression, and metastasis, with cancer-associated fibroblasts (CAFs) representing one of the most abundant and influential stromal cell populations. Recent advances in single cell sequencing and spatial transcriptomics in combination with mechanistic studies have revealed the extent of CAF functional heterogeneity, identifying distinct subpopulations with specialized roles in tumor promotion, immune modulation, and therapy resistance. This review synthesizes current understanding of CAF biology, highlighting recent discoveries regarding their spatial organization, temporal dynamics, and immunoregulatory functions. We discuss emerging therapeutic strategies targeting CAF subpopulations, including approaches for CAF elimination and reprogramming. These advances provide new opportunities for developing more effective cancer treatments that account for stromal complexity and CAF-mediated resistance mechanisms.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102601
  27. Best Pract Res Clin Gastroenterol. 2025 Sep;pii: S1521-6918(25)00075-7. [Epub ahead of print]78 102048
    Modeling gut inflammation using intestinal organoids: Advances, challenges, and future perspectives.
    Justina Guzauskiene, Deimante Valentelyte, Goda Butaite, Ugne Kulokiene, Viltaute Laukaitiene, Ruta Inciuraite, Jurgita Skieceviciene.
      Intestinal organoids have emerged as powerful in vitro system for studying epithelial biology in a tissue-relevant context. Derived from adult stem cells or patient-specific induced pluripotent stem cells, these three-dimensional structures recapitulate key features of the intestinal epithelium, including crypt-villus architecture, cellular diversity, and functional barrier properties. Recent advances have enabled the modeling of gut inflammation using organoids through defined cytokine stimulation, co-culture with immune cells, and exposure to microbial components. These approaches have provided insights into epithelial barrier dysfunction, immune-epithelial crosstalk, and disease-specific responses, particularly in inflammatory bowel disease. Innovations such as gene-editing technologies, single-cell and spatial transcriptomics, and microengineered platforms like organoid-on-chip systems have advanced organoid-based research in various contexts, laying a strong foundation for their future application in modeling inflammation. Despite these advances, challenges remain in achieving long-term immune co-culture, media compatibility, and standardized readouts. This article highlights current strategies, key limitations, and future directions for using intestinal organoids to model gut inflammation and guide translational research.
    Keywords:  Disease modeling; Drug screening; Epithelial barrier function; Gut inflammation; Host-microbe interactions; Immune-epithelial crosstalk; Inflammatory cytokine stimulation; Intestinal organoids; Organoid co-culture models
    DOI:  https://doi.org/10.1016/j.bpg.2025.102048
  28. Cancer Pathog Ther. 2026 Jan;4(1): 14-30
    Emerging risk factors and the role of gut microbiota in immunomodulation and therapeutic implications in colorectal cancer.
    Sonakshi Modeel, Sneha Siwach, Padma Dolkar, Meenu Chaurasia, Pankaj Yadav, Apoorva Atri, Aarzoo Yadav, Tarana Negi, Ram Krishan Negi.
      The pathophysiology of many ailments, including neurological, gastrointestinal, and metabolic problems, is well known to be influenced by intestinal dysbiosis. Clinical research has provided evidence suggesting a strong correlation between dysbiosis of the gut microbiome and colorectal cancer (CRC) development. The active reprogramming of metabolic pathways to boost glycolysis, fatty acid production, lipogenesis, and glutaminolysis constitutes a major metabolic shift in cancer development, including CRC. The complex combination of different factors leads to CRC, making it an environmental disease. These factors include food and lifestyle choices, genetics and family history, age, underlying intestinal diseases, and dysbiosis of the gut microbiota. One of the primary risk factors for carcinoma development is diet, which impacts an individual's gut microbiome. In addition to impacting CRC formation, the gut microbiome also has immunomodulatory effects, including various immunological interactions and the underlying mechanisms governing them. Microbial interactions in CRC have been extensively studied, yet numerous unresolved queries exist on how gut bacteria can influence treatment. It is possible to perform microbiome-driven immunotherapies focusing on probiotics, prebiotics, and synbiotics. However, large-scale treatment utilization in CRC patients is limited by several issues, including variations in the microbial makeup of each patient's gut and a lack of established methods. The study highlights the impact of several risk factors, including dysbiosis of the gut microbiome and different approaches to halting and treating CRC progression with a focus on diet changes and modulation of the gut flora. Given the foregoing, we propose that if research gaps are addressed and immunotherapy is paired with microbial interventions, microbiota-based therapeutics could potentially impede the growth of tumors and treat CRC.
    Keywords:  CRC therapy; Colorectal cancer; Gastrointestinal microbiome; Immunomodulation; Probiotics; Risk factors
    DOI:  https://doi.org/10.1016/j.cpt.2025.06.007
  29. Ann Med. 2025 Dec;57(1): 2591308
    Cellular characteristics of the immune microenvironment of colorectal cancer and progress in immunotherapy research.
    Chunbaixue Yang, Jianchun Fan, Yixuan Zhang, Yixiao Zhang, Lei Xia, Xinran Cao, Xueliang Wu.
       BACKGROUND: Colorectal cancer (CRC) continues to represent a major cause of cancer-related mortality worldwide, with its progression and therapeutic outcomes strongly shaped by the complexity and heterogeneity of the tumor immune microenvironment (TME). This review critically examines the cellular and molecular mechanisms driving immune evasion in CRC, emphasizing the dual roles of immune cell populations-including tumor-associated macrophages, neutrophils, dendritic cells, T cells, B cells, and natural killer cells-as well as non-cellular elements such as the extracellular matrix and extracellular vesicles.
    OBJECTIVE: A key objective is to evaluate recent developments in immunotherapeutic approaches, including immune checkpoint inhibitors, tumor vaccines, adoptive cell transfer, and novel combinatorial regimens, while addressing their therapeutic promise and inherent limitations, especially in microsatellite-stable (MSS) tumors that exhibit primary resistance to standard immunotherapies. Further analysis integrates perspectives on metabolic reprogramming within the TME, epigenetic alterations, and advances in engineered cellular therapies, thereby providing a comprehensive framework for overcoming immunosuppressive mechanisms.
    DISCUSSION AND CONCLUSION: Special consideration is directed toward the translational value of targeting immune-metabolic interactions and spatial dynamics within the TME. Ultimately, this work synthesizes current knowledge and outlines forward-looking strategies to advance personalized, multi-target immunotherapy, with the potential to reshape clinical paradigms in CRC management.
    Keywords:  Colorectal cancer; immunotherapy; research progress; tumor microenvironment
    DOI:  https://doi.org/10.1080/07853890.2025.2591308
  30. Cancer Cell Int. 2025 Dec 04.
    Non-invasive colorectal cancer screening methods: focusing on diagnostic genetic and epigenetic markers.
    Ghazaleh Behrouzian Fard, Razieh Amirfakhrian, Mahdi Hosseini Bafghi, Mehran Gholamin.
      Colorectal cancer (CRC) is the third most prevalent cancer and one of the leading causes of cancer-related mortality in the world. Early detection is crucial in preventing deaths, but current screening methods have various limitations. So today, much attention is focused on genetic changes, including mutations in oncogenes and tumor suppressor genes, and epigenetic modifications such as aberrant methylation and alterations in the expression of specific microRNAs that contribute to CRC development. This has led to the discovery of more specific and sensitive molecular biomarkers. Furthermore, the use of liquid biopsy, which has a high potential for identifying molecular tumor markers, provides a perspective for overcoming the limitations of conventional screening methods. In this review, we first discuss the intricate molecular processes involved in the development of colorectal tumors. We then delve into the concept of liquid biopsy, exploring its traceable components such as extracellular vesicles, circulating tumor cells, circulating tumor DNAs, and circulating tumor RNAs. We also examine various methods for analyzing these components to identify molecular biomarkers for CRC screening. Additionally, we refer to the development of new diagnostic kits for CRC, such as Epi proColon, ColoSure, and Cologuard, which offer non-invasive utilization of genetic and epigenetic biomarkers. Lastly, we address the current challenges faced in using these biomarkers in a clinical setting. Despite the obstacles, these non-invasive and reliable markers have the potential to enable early detection of CRC and likely increase screening uptake, potentially replacing current modalities.
    Keywords:  Colorectal cancer; DNA methylation; Liquid biopsy; MicroRNAs; Non-invasive screening
    DOI:  https://doi.org/10.1186/s12935-025-04097-y
  31. bioRxiv. 2025 Nov 21. pii: 2025.11.20.689581. [Epub ahead of print]
    Decrypting cellular engagement and recruitment from spatially resolved transcriptomics.
    Jia Yao, Ji Seon Shim, James Zhu, Sung Wook Kang, Kelli McCord, Woo Yong Chang, Jong Min Choi, Claire Lee, Hee-Jin Jang, William H Hudson, Bryan M Burt, Tao Yue, Changwei Li, Hyun-Sung Lee, Tao Wang.
      The recruitment of the various types of cells into the tissue microenvironment and how these cells engage with other cells in the tissue sites play critical biological roles. However, it is difficult to study these processes on a genome-wide scale using traditional low-throughput experiments. Spatially resolved transcriptomics (SRT), especially high definition SRT, have offered opportunities in deciphering the determinants of cellular localization at unprecedented scale and resolution. But it is challenging to digest the abundance of transcriptomics and positional information of the numerous cells in SRT data. To address this gap, we developed a fully interpretable multi-instance deep learner, spacer. We deployed spacer to a panel of 17 high definition and 20 low definition SRT datasets, for studying how stromal and immune cells were recruited into tumors and heart during myocarditis. We coupled spacer with orthogonal immuno-peptidomics, spatial T cell receptor (TCR) sequencing, and single cell sequencing experiments. We discovered genes that encode more immunogenic peptides and that are involved in developmental pathways are more potent in recruiting T cells to local tumor sites. We also found, however, that tumor cells tend to down-regulate such genes to avoid T cell recognition. On the other hand, expression of mucins in the tumor cells was found to repel T cell localization. For the engaging cell side, we uncovered a tumor-engaging gene signature for T cells, validated by spatial-TCR-seq data. Spacer also revealed that CD4 + T cells, though fewer in numbers, are more responsive than CD8 + T cells in the heart during myocarditis. Collectively, this study establishes a spatially resolved paradigm for studying cellular localization mechanisms in situ and paves the way for the construction of a comprehensive cellular recruiting-engaging interaction atlas in solid tissues.
    DOI:  https://doi.org/10.1101/2025.11.20.689581
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