bims-enbcad Biomed News
on Engineering biology for causal discovery
Issue of 2025–11–30
twenty-one papers selected by
Xiao Qin, University of Oxford
  1. From slices to deep dishes: spatial transcriptomics and translatomics of thick tissue blocks.
  2. Polyclonal origins of human premalignant colorectal lesions.
  3. Dynamic remodelling of epithelial plasticity in colorectal cancer from single-cell and spatially resolved perspectives.
  4. Studies Challenge Cancer-Microbiome Links.
  5. Single-cell insights into tumor microenvironment heterogeneity and plasticity: transforming precision therapy in gastrointestinal cancers.
  6. Leveraging WNT Hyperactivation to Kill Colorectal Cancer While Rejuvenating Healthy Intestine.
  7. Cell state plasticity emerging from co-regulated, competitive, and configurable interactions within the AP-1 network.
  8. Age distinguishes selection from causation in cancer genomes.
  9. Lifting regenerative barriers promotes epithelial cell fate plasticity supporting lineage conversion.
  10. Comprehensive benchmarking of somatic mutation detection by the SMaHT Network.
  11. A comprehensive view of somatic mosaicism by single-cell DNA analysis.
  12. The Wnt/APC destruction complex targets SREBP2 in a β-catenin-independent pathway to control cholesterol metabolism.
  13. The Gut Microbiome in Early-Onset Colorectal Cancer: Distinct Signatures, Targeted Prevention and Therapeutic Strategies.
  14. Aptamer-Based Strategies for Colorectal Cancer Detection: Emerging Technologies and Future Directions.
  15. Lgr5+ Stem Cells Maintain Apex Position in Cell Hierarchy of the Intestinal Epithelium During Homeostasis and Injury.
  16. Could artificial intelligence-powered colonoscopies change the future of colorectal cancer screening?
  17. Long-read metagenomics reveals phage dynamics in the human gut microbiome.
  18. Large-scale single-cell phylogenetic mapping of clonal evolution in the human aging esophagus.
  19. Programmable conjugative CRISPR interference targeting genotoxin in the gut.
  20. Multiple primary tumours in early-onset colorectal cancer: deciphering the risk.
  21. Single-cell transcriptomic analysis reveals the heterogeneity and functional characteristics of macrophage subpopulations in colon cancer.
  1. Nat Methods. 2025 Nov 24.
    From slices to deep dishes: spatial transcriptomics and translatomics of thick tissue blocks.
    Maroš Pleška, Sanja Vickovic.
      
    DOI:  https://doi.org/10.1038/s41592-025-02815-y
  2. Nature. 2025 Nov 25.
    Polyclonal origins of human premalignant colorectal lesions.
    Debra Van Egeren, Ryan O Schenck, Aziz Khan, Aaron M Horning, Shanlan Mo, Clemens L Weiß, Edward D Esplin, Winston R Becker, Si Wu, Casey Hanson, Nasim Barapour, Lihua Jiang, Kévin Contrepois, Hayan Lee, Stephanie A Nevins, Tuhin K Guha, Hao Zhang, Zhen He, Zhicheng Ma, Emma Monte, Thomas V Karathanos, Rozelle Laquindanum, Meredith A Mills, Hassan Chaib, Roxanne Chiu, Ruiqi Jian, Joanne Chan, Mathew Ellenberger, Bahareh Bahmani, Basil Michael, Annika K Weimer, D Glen Esplin, Samuel Lancaster, Jeanne Shen, Uri Ladabaum, Teri A Longacre, Anshul Kundaje, William J Greenleaf, Zheng Hu, James M Ford, Michael P Snyder, Christina Curtis.
      Cancer is generally thought to be caused by expansion of a single mutant cell1. However, analyses of early colorectal cancer lesions suggest that tumors may instead originate from multiple, genetically distinct cell populations2,3. Detecting polyclonal tumor initiation is challenging in patients, as it requires profiling early-stage lesions before clonal sweeps obscure diversity. To investigate this, we analyzed normal colorectal mucosa, benign and dysplastic premalignant polyps, and malignant adenocarcinomas (123 samples) from six individuals with familial adenomatous polyposis (FAP). Individuals with FAP have a germline heterozygous APC mutation, predisposing them to colorectal cancer and numerous premalignant polyps by early adulthood4. Whole-genome and/or whole-exome sequencing revealed that many premalignant polyps-40% with benign histology and 28% with dysplasia-were composed of multiple genetic lineages that diverged early, consistent with polyclonal origins. This conclusion was reinforced by whole-genome sequencing of single crypts from multiple polyps in additional patients which showed limited sharing of mutations among crypts within the same lesion. In some cases, multiple distinct APC mutations co-existed in different lineages of a single polyp, consistent with polyclonality. These findings reshape our understanding of early neoplastic events, demonstrating that tumor initiation can arise from the convergence of diverse mutant clones. They also suggest that cell-intrinsic growth advantages alone may not fully explain tumor initiation, highlighting the importance of microenvironmental and tissue-level factors in early cancer evolution.
    DOI:  https://doi.org/10.1038/s41586-025-09930-y
  3. J Transl Med. 2025 Nov 24. 23(1): 1341
    Dynamic remodelling of epithelial plasticity in colorectal cancer from single-cell and spatially resolved perspectives.
    Chengyuan Xu, Yun Pan, Siqi Zhang, Moubin Lin, Hailong Liu, Zicheng Yu.
      
    Keywords:  Colorectal cancer; Copy number variation; Epithelial plasticity; SCAND1; Single-cell transcriptomics; Spatial transcriptomics
    DOI:  https://doi.org/10.1186/s12967-025-07380-8
  4. Cancer Discov. 2025 Nov 25. OF1
    Studies Challenge Cancer-Microbiome Links.
      Two recent studies analyzing cancer genome data suggest that microbial DNA is not a common feature across most tumors, challenging earlier suggestions of a pan-cancer microbiome. Colorectal cancer stands as an exception, with one study providing strong evidence of a microbial signature. Oral cancer may also be an exception. Both studies point to contamination as a key driver of false signals.
    DOI:  https://doi.org/10.1158/2159-8290.CD-NW2025-0104
  5. J Exp Clin Cancer Res. 2025 Nov 28. 44(1): 314
    Single-cell insights into tumor microenvironment heterogeneity and plasticity: transforming precision therapy in gastrointestinal cancers.
    Jialei Weng, Feng Ju, Zicheng Lyu, Ningbo Fan, Daniel J Smit, Wenxin Xu, Xiaolin Wu, Philip Becker, Yinan Xu, Michal R Schweiger, Axel M Hillmer, Ralf Harwig, Sheraz Gul, Alexander Link, Lydia Meder, Nan Fang, Qiongzhu Dong, Christiane J Bruns, Ning Ren, Yue Zhao.
      The development and progression of gastrointestinal (GI) cancers not only depend on the malignancy of the tumor cells, but is also defined by the complex and adaptive nature of the tumor microenvironment (TME). The TME in GI cancers exhibits a complex internal structure, typically comprising cancer cells, cancer stem cells, cancer-associated fibroblasts, immune cells, and endothelial cells, all embedded within a dynamic extracellular matrix. This intricate ecosystem fuels tumor initiation, progression, metastasis, recurrence and therapy response through the heterogeneity and plasticity. Recent advances in single-cell sequencing have provided unprecedented resolution in profiling the cellular diversity and interactions within the TME. These technologies have uncovered previously unknown cell subtypes and intricate communication networks that drive therapy resistance and tumor relapse. In this review, we summarize and discuss the latest findings from single-cell sequencing of key cellular players and their interactions within the TME of GI cancers. We highlight single cell insights that are reshaping our understanding of tumor biology, with particular focus on their implications for overcoming therapy resistance and improving clinical outcomes. We believe that a deeper understanding of TME heterogeneity and plasticity at the single-cell level promises to transform the landscape of precision treatment in GI cancers.
    Keywords:  Cancer-associated fibroblasts; Cell subsets; Gastrointestinal cancers; Heterogeneity; Plasticity; Single-cell RNA sequencing; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s13046-025-03567-5
  6. bioRxiv. 2025 Oct 06. pii: 2025.10.05.680591. [Epub ahead of print]
    Leveraging WNT Hyperactivation to Kill Colorectal Cancer While Rejuvenating Healthy Intestine.
    George Eng, Jonathan Braverman, Manish Gala, Omer Yilmaz.
      WNT signaling maintains intestinal homeostasis yet drives colorectal cancer (CRC) when constitutively activated by APC mutations. We overturn the fundamental assumption that APC-mutant tumors exist at maximal WNT activation, revealing instead that cancer cells occupy a precarious "WNT-just-right" zone along a signaling continuum. This discovery exposes an unprecedented therapeutic vulnerability: while normal intestinal epithelium thrives with enhanced WNT signaling, APC-mutant tumor cells undergo apoptosis when pushed beyond their oncogenic setpoint, a phenomenon we term "over-WNTing." Through systematic organoid-based screening, we identified that WNT hyperactivation through multiple approaches: GSK3 inhibition, concentrated WNT proteins, or APC knockdown in GSK3-null backgrounds, selectively kills tumor cells by hyperactivating the driving pathway of CRC. Mechanistically, over-WNTing in APC-mutant cells triggers spillover into non-canonical planar cell polarity signaling, where RHOC upregulation induces ROCK1/2-mediated apoptosis. We demonstrate therapeutic efficacy across the neoplastic continuum, from adenomas to metastatic CRC, including patient-derived tumors, validating GSK3 inhibition with a novel nanoparticle formulation. This discovery enables the first cancer therapy that simultaneously enhances normal tissue function while eliminating tumors. "Over-WNTing" effectively treats adenomas and both mouse and patient-derived CRC, establishing a therapeutic paradigm that exploits fundamental differences in cellular WNT biology to achieve the dual benefit of eliminating cancer while promoting healthy tissue regeneration.
    DOI:  https://doi.org/10.1101/2025.10.05.680591
  7. bioRxiv. 2025 Nov 07. pii: 2025.11.06.686987. [Epub ahead of print]
    Cell state plasticity emerging from co-regulated, competitive, and configurable interactions within the AP-1 network.
    Yonatan N Degefu, Magda Bujnowska, Douglas G Baumann, Mohammad Fallahi-Sichani.
      Cell state plasticity drives metastasis and therapy resistance in cancers. In melanoma, these behaviors map onto a melanocytic-to-mesenchymal-like continuum regulated by AP-1 transcription factors. However, how the AP-1 network encodes a limited set of discrete states, why their distributions vary across tumors, and what drives phenotypically consequential AP-1 state transitions remain unclear. We develop a mechanistic ODE model of the AP-1 network capturing their dimerization-controlled, co-regulated, competitive interactions. Calibrated to heterogeneous single-cell data across genetically diverse melanoma populations and combined with statistical learning, the model reveals network features explaining population-specific AP-1 state distributions. These features correlate with MAPK activity across tumor lines and with variability within clones, linking MAPK signaling to AP-1 states. The model predicts and experiments validate adaptive AP-1 reconfiguration under MAPK inhibition, inducing a dedifferentiated, therapy-resistant state that can be blocked by model-guided AP-1 perturbations. These results establish AP-1 as a configurable network and provide a computational framework for predicting and modulating AP-1 driven cell state plasticity.
    DOI:  https://doi.org/10.1101/2025.11.06.686987
  8. bioRxiv. 2025 Oct 06. pii: 2025.10.06.680730. [Epub ahead of print]
    Age distinguishes selection from causation in cancer genomes.
    David Cheek, Martin Blohmer, Martin Nowak, Tibor Antal, Kamila Naxerova.
      Cancer genome sequencing efforts have revealed hundreds of genes under positive selection, many of which are now being developed as therapeutic targets. However, positively selected mutations also populate our aging tissues in the absence of cancer. For most mutations, it is currently unknown whether they are recurrently found in cancer genomes because they cause cancer or because they expand during normal tissue evolution and are passively inherited. Here, we develop a mathematical and statistical framework that distinguishes these two factors. We discover - across thousands of cancer and normal tissue genomes - that mutations that most strongly increase cancer risk are enriched in younger patients' cancers, whereas mutations that are positively selected in normal tissue without causing cancer are enriched in older patients. Focusing on a particularly data-rich cancer type, acute myeloid leukemia, we show that genetic differences between young- and adult-onset cancers can largely be explained by the cumulative effects of normal tissue evolution, contradicting the long-standing notion that childhood cancers require a distinct set of causal mutations. Our framework establishes patient age as a powerful resource for clarifying whether positively selected mutations in cancer genomes are truly disease-promoting.
    DOI:  https://doi.org/10.1101/2025.10.06.680730
  9. Nat Commun. 2025 Nov 27.
    Lifting regenerative barriers promotes epithelial cell fate plasticity supporting lineage conversion.
    Maria T Bejar, Paula Jimenez-Gomez, Ilias Moutsopoulos, Harikrishnan Ajith, Bartomeu Colom, Jamie McGinn, Seungmin Han, Greta Skrupskelyte, Fernando J Calero-Nieto, Berthold Göttgens, Irina I Mohorianu, Benjamin D Simons, Maria P Alcolea.
      The ability of adult epithelial cells to rewire their cell fate programme in response to injury has emerged as a new paradigm in stem cell biology. This plasticity supersedes the concept of strict stem cell hierarchies, granting cells access to a wider repertoire of fate choices. Yet, in order to prevent a disordered cellular response, this process must be finely regulated. Here we investigate the little-known regulatory processes that restrict fate permissibility in adult cells, and keep plasticity in check. Using a 3D regenerative culture system, that enables co-culturing epithelium and stroma of different origins, we demonstrate that oesophageal cells exposed to the ectopic signals of the dermis are capable of switching their identity towards skin. Lineage tracing experiments and histological analysis, however, reveal that the oesophageal-to-skin lineage conversion process is highly inefficient, pointing to the existence of barriers limiting cell fate re-specification. Single-cell RNA sequencing capturing the temporality of this process shows that cells transitioning towards skin identity resist the natural progression towards tissue maturation by remaining in a persistent regenerative state marked by a particularly strong hypoxic signature. Gain and loss of function experiments demonstrate that the HIF1a-SOX9 axis acts as a key modulator of epithelial cell fate plasticity, restricting changes in identity during tissue regeneration. Taken together, our results reveal the existence of lineage conversion barriers that must be resolved for cells to respond to signals instructing alternative fate choices, shedding light on the principles underlying the full regenerative capacity of adult epithelial cells.
    DOI:  https://doi.org/10.1038/s41467-025-66446-9
  10. bioRxiv. 2025 Oct 10. pii: 2025.10.09.678885. [Epub ahead of print]
    Comprehensive benchmarking of somatic mutation detection by the SMaHT Network.
    Somatic Mosaicism across Human Tissues Network
      Somatic mosaicism is increasingly recognized as a fundamental feature of human biology, yet the detection of somatic mutations remains challenging. The SMaHT Network conducted four large-scale benchmarking experiments to evaluate sequencing technologies, experimental approaches, and computational methods for detecting diverse somatic mutations. Cumulative sequencing coverage exceeded 1,000× with short reads and 100-400× with long reads for each of nine analyzed samples. We defined optimal strategies for integrating bulk short- and long-read sequencing for mutation detection and demonstrated that using donor-specific assemblies and human pangenome improved variant calling and extended mutation catalogs to challenging genomic regions. We benchmarked six duplex-seq technologies and showed that single-cell sequencing resolves cell type-specific mutational patterns and heterogeneity. Our results indicate that bulk, single-cell, and duplex analyses are complementary - and leveraging all three provides comprehensive characterization of mosaicism within a tissue. Together, these findings provide a roadmap for accurate, genome-wide somatic mutation discovery and analysis.
    DOI:  https://doi.org/10.1101/2025.10.09.678885
  11. bioRxiv. 2025 Nov 03. pii: 2025.10.31.685648. [Epub ahead of print]
    A comprehensive view of somatic mosaicism by single-cell DNA analysis.
    SMaHT Single Cell Focus Group
      Single-cell DNA sequencing offers a powerful means of studying somatic mosaicism but requires careful analysis to mitigate DNA amplification-related artifacts. We performed primary template-directed amplification (PTA) and sequencing of 102 nuclei from postmortem lung and colon tissues of a 74-year-old male. Single-cell mutation burdens and spectra were validated by duplex sequencing and revealed heterogeneity across organs and cells, including signatures of APOBEC activity and tobacco exposure. Cells from both tissues exhibited chromosomal aneuploidies, loss of chromosome Y, and chromosomal rearrangements including rearrangements of the T-cell receptor loci indicative of T-cells. Shared embryonic mutations between cells enabled reconstruction of cellular ancestries from the zygote, which were validated by bulk sequencing. Collectively, we demonstrate a comprehensive approach for single-cell genomics that yields an expansive view of diverse somatic mutation types from development through aging across diverse tissues-insights that are obscured in bulk sequencing and only partially captured by other single-cell methods.
    DOI:  https://doi.org/10.1101/2025.10.31.685648
  12. bioRxiv. 2025 Nov 18. pii: 2025.10.12.681896. [Epub ahead of print]
    The Wnt/APC destruction complex targets SREBP2 in a β-catenin-independent pathway to control cholesterol metabolism.
    Ahmed Rattani, Cora Anderson, William V Trim, Esteban Garita, Shinya Imada, Saleh Khawaled, Heaji Shin, Jiuchun Zhang, Ömer H Yilmaz, Marc Kirschner.
      APC, the core scaffold of the Wnt destruction complex, targets the transcriptional co-activator β-catenin for proteolysis. There is no convincing evidence that APC directs degradation of other substrates. Using a reconstituted cytosolic extract-based system and complementary in vivo and cellular assays, we show that SREBP2, the master regulator of cholesterol biosynthesis, is a direct APC-AXIN1 substrate. APC-dependent SREBP2 degradation is conserved in Xenopus embryos, mouse colon, and human colorectal cancer cells and restricts SREBP2 target-gene expression, cholesterol synthesis, and tissue cholesterol levels. Mechanistically, APC and AXIN1 promote SREBP2 degradation via a conserved phosphodegron, which marks SREBP2 for ubiquitination by the E3 enzyme, FBXW7. Like β-catenin, SREBP2 is stabilized by extracellular Wnt ligands; unlike β-catenin, its regulation is independent of GSK3β and CK1α and requires the entire APC mutational cluster region (MCR), whereas β-catenin turnover can operate with only a partial MCR. These findings define a β-catenin-independent branch of Wnt signaling that couples APC to sterol metabolism, providing a mechanistic rationale to target the mevalonate/SREBP2 axis in APC-mutant colorectal cancer.
    DOI:  https://doi.org/10.1101/2025.10.12.681896
  13. J Pers Med. 2025 Nov 12. pii: 552. [Epub ahead of print]15(11):
    The Gut Microbiome in Early-Onset Colorectal Cancer: Distinct Signatures, Targeted Prevention and Therapeutic Strategies.
    Sara Lauricella, Francesco Brucchi, Roberto Cirocchi, Diletta Cassini, Marco Vitellaro.
      Background/Objectives: The incidence of early-onset colorectal cancer (EOCRC) is rising worldwide, although its biological and clinical features remain incompletely understood. Emerging evidence implicates gut microbial dysbiosis as a key driver of EOCRC pathogenesis, acting through complex interactions with host genetics, mucosal immunity, and early-life exposures. This review synthesizes current evidence on EOCRC-specific microbial signatures, delineates host-microbiome interactions, and evaluates how these insights may inform precision prevention, early detection, and therapeutic strategies. Methods: A systematic literature search was conducted in PubMed, Scopus, and Web of Science up to August 2025, using combinations of "early-onset colorectal cancer," "gut microbiome," "dysbiosis," and "host-microbiome interactions." Both clinical and preclinical studies were included. Extracted data encompassed microbial composition, mechanistic insights, host-related factors, and microbiome-targeted interventions. Evidence was synthesized narratively to highlight consistent patterns, methodological limitations, and translational implications. Results: EOCRC is consistently associated with enrichment of pro-inflammatory and genotoxic taxa (e.g., Fusobacterium nucleatum, colibactin-producing Escherichia coli, enterotoxigenic Bacteroides fragilis) and depletion of short-chain fatty acid-producing commensals. Multi-omics analyses reveal distinct host-microbiome signatures influenced by germline predisposition, mucosal immunity, sex, and early-life exposures. However, substantial methodological heterogeneity persists. Collectively, these data point to candidate microbial biomarkers for early detection and support the rationale for microbiome-targeted preventive and adjunctive therapeutic approaches. Conclusions: EOCRC harbors unique microbial and host-environmental features that distinguish it from late-onset disease. Integrating host determinants with microbiome signatures provides a framework for precision prevention and tailored therapeutic strategies. Future priorities include harmonizing methodologies, validating microbial biomarkers in asymptomatic young adults, and rigorously testing microbiome-targeted interventions in clinical trials.
    Keywords:  dysbiosis; early-onset colorectal cancer; gut microbiome; microbial signatures; microbiota
    DOI:  https://doi.org/10.3390/jpm15110552
  14. Biosensors (Basel). 2025 Nov 01. pii: 726. [Epub ahead of print]15(11):
    Aptamer-Based Strategies for Colorectal Cancer Detection: Emerging Technologies and Future Directions.
    María Jesús Lobo-Castañón, Ana Díaz-Fernández.
      Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide, with patient outcomes highly dependent on early and accurate diagnosis. However, existing diagnostic methods, such as colonoscopy, fecal occult blood testing, and imaging, are often invasive, costly, or lack sufficient sensitivity and specificity, particularly in early-stage disease. In this context, aptamers, which are synthetic single-stranded oligonucleotides capable of binding to specific targets with high affinity, have emerged as a powerful alternative to antibodies for biosensing applications. This review provides a comprehensive overview of aptamer-based strategies for CRC detection, spanning from biomarker discovery to clinical translation. We first examine established and emerging CRC biomarkers, including those approved by regulatory agencies, described in patents, and shared across multiple cancer types. We then discuss recent advances in aptamer selection and design, with a focus on SELEX variants and in silico optimization approaches tailored to CRC-relevant targets. The integration of aptamers into cutting-edge sensing platforms, such as electrochemical, optical, and nanomaterial-enhanced aptasensors, is highlighted, with emphasis on recent innovations that enhance sensitivity, portability, and multiplexing capabilities. Furthermore, we explore the convergence of aptasensing with microfluidics, and wearable technologies to enable intelligent, miniaturized diagnostic systems. Finally, we consider the clinical and regulatory pathways for point-of-care implementation, as well as current challenges and opportunities for advancing the field. By outlining the technological and translational trajectory of aptamer-based CRC diagnostics, this review aims to provide a roadmap for future research and interdisciplinary collaboration in precision oncology.
    Keywords:  CRC biomarkers; SELEX; aptamer; liquid biopsy
    DOI:  https://doi.org/10.3390/bios15110726
  15. bioRxiv. 2025 Nov 11. pii: 2025.11.09.687498. [Epub ahead of print]
    Lgr5+ Stem Cells Maintain Apex Position in Cell Hierarchy of the Intestinal Epithelium During Homeostasis and Injury.
    Julian Chua, Lucy Driver, Masahiro Narimatsu, Mardi Fink, Lixia Luo, Jordan Tran, Arshdeep Kaur, Rida Habib, Jatin Roper, David G Kirsch, Jeffrey L Wrana, Chang-Lung Lee, Arshad Ayyaz.
      The cellular origin of intestinal epithelial homeostasis and regeneration has been a subject of continued debate, with recent models challenging the primacy of WNT-dependent Lgr5⁺ crypt base columnar (CBC) cells as the central intestinal stem cell population. Here, we revisit this question through quantitative integration of single-cell transcriptomic, chromatin accessibility, spatial, and lineage-tracing analyses across the proximal-to-distal axis of the small intestinal epithelium. Our data show that under homeostatic conditions, Lgr5⁺ cells exclusively sustain epithelial self-renewal in nearly all crypt-villus units along the entire length of the small intestine, a process for which R-spondin is indispensable. Following irradiation or chemotoxic injury, surviving Lgr5⁺ cells and their progeny reprogram into transient fetal-like cell states that initiate epithelial repair. Crucially, successful regeneration depends on the reactivation of canonical WNT/β-catenin signaling, as evidenced by increased TCF motif accessibility and upregulation of WNT target genes in newly forming Lgr5 + stem cells. Accordingly, pharmacological inhibition of WNT signaling blocks the reconstitution of Lgr5⁺ cells and crypt regeneration, leading to epithelial collapse. These findings reconcile prior controversies by demonstrating the central role of Lgr5⁺ CBC cells in epithelial self-renewal and regeneration following injury.
    DOI:  https://doi.org/10.1101/2025.11.09.687498
  16. World J Gastroenterol. 2025 Nov 14. 31(42): 111291
    Could artificial intelligence-powered colonoscopies change the future of colorectal cancer screening?
    Mircea Mănuc, Cătălin-Andrei Duței, Teodora-Ecaterina Mănuc, Andreea-Elena Chifulescu, Florin Andrei Grama.
      Colorectal cancer is a major cause of cancer-related mortality worldwide, underscoring the importance of early and effective colorectal cancer screening to improve survival rates. Traditional colorectal cancer screening methods include non-invasive tests, such as the fecal immunochemical test (FIT), as well as diagnostic procedures like colonoscopy. Colonoscopy remains the gold standard for detecting and treating precancerous polyps and early-stage cancer, regardless of whether it is used as the first screening test or the second test following a positive FIT. However, its effectiveness can be affected by factors such as operator skill, patient variability, and limited lesion visibility, resulting in a significant rate of missed lesion rates and highlighting the need for more efficient and accurate screening techniques. This review is aimed to assess the current challenges of traditional screening methods with the impact of artificial intelligence (AI) in the diagnostic flow. The literature on AI-powered tools for colorectal cancer screening, including novel applications, emerging programs, and recent guidelines, has been reviewed to highlight both the advantages and limitations of implementing this technology in healthcare. Recent advances in AI have introduced soft AI colonoscopy, with the purpose of improving lesion recognition (computer-aided detection) and/or improving optical diagnosis (computer-aided diagnosis). AI-powered colonoscopy systems employ deep learning algorithms to analyze real-time endoscopic images, enhancing detection rates for adenomas, serrated lesions and cancer by reducing human error. AI-assisted colonoscopy enhances adenoma detection, enabling earlier intervention and improved patient outcomes. The benefits are particularly pronounced for less-experienced practitioners, as the detection rates for AI-assisted colonoscopy are similar to experts. AI integration also helps in the teaching process, in developing standardized procedures, and improving screening procedure accuracy and efficiency across different healthcare providers. However, there are challenges and limitations, such as the cost of AI implementation, data privacy concerns, and the need for extensive clinical validation. As AI technology continues to evolve, its transformation of the colorectal cancer screening system could revolutionize the field, making early detection more accessible and reducing mortality, on the condition that the above issues are addressed before widespread use.
    Keywords:  Adenoma detection rate; Artificial intelligence; Artificial intelligence powered colonoscopy; Colorectal cancer; Colorectal cancer screening
    DOI:  https://doi.org/10.3748/wjg.v31.i42.111291
  17. Nature. 2025 Nov 26.
    Long-read metagenomics reveals phage dynamics in the human gut microbiome.
    Jakob Wirbel, Angela S Hickey, Daniel Chang, Nora J Enright, Mai Dvorak, Rachael B Chanin, Danica T Schmidtke, Ami S Bhatt.
      Gut bacteriophages profoundly impact microbial ecology and health1-3; yet, they are understudied. Using deep long-read bulk metagenomic sequencing, we tracked prophage integration dynamics in stool samples from six healthy individuals, spanning a 2-year timescale. Although most prophages remained stably integrated into their hosts, approximately 5% of phages were dynamically gained or lost from persistent bacterial hosts. Within a sample, we found that bacterial hosts with and without a given prophage coexisted simultaneously. Furthermore, phage induction, when detected, occurred predominantly at low levels (1-3× coverage compared to the host region), in line with theoretical expectations4. We identified multiple instances of integration of the same phage into bacteria of different taxonomic families, challenging the dogma that phages are specific to a host of a given species or strain5. Finally, we describe a new class of 'IScream phages', which co-opt bacterial IS30 transposases to mediate their mobilization, representing a previously unrecognized form of phage domestication of selfish bacterial elements. Taken together, these findings illuminate fundamental aspects of phage-bacterial dynamics in the human gut microbiome and expand our understanding of the evolutionary mechanisms that drive horizontal gene transfer and microbial genome plasticity.
    DOI:  https://doi.org/10.1038/s41586-025-09786-2
  18. bioRxiv. 2025 Oct 13. pii: 2025.10.11.681805. [Epub ahead of print]
    Large-scale single-cell phylogenetic mapping of clonal evolution in the human aging esophagus.
    Tamara Prieto, Dennis J Yuan, John Zinno, Clayton Hughes, Nicholas Midler, Sheng Kao, Jani Huuhtanen, Ramya Raviram, Foteini Fotopoulou, Neil Ruthen, Srinivas Rajagopalan, Joshua S Schiffman, Andrew R D'Avino, Sang-Ho Yoon, Jesus Sotelo, Nathaniel D Omans, Noelle Wheeler, Alejandro Garces, Barun Pradhan, Alexandre Pellan Cheng, Nicolas Robine, Catherine Potenski, Katharine Godfrey, Nobuyuki Kakiuchi, Akira Yokoyama, Seishi Ogawa, Julian Abrams, Ivan Raimondi, Dan A Landau.
      The human somatic genome evolves throughout our lifespan, producing mosaic individuals comprising clones harboring different mutations across tissues. While clonal expansions in the hematopoietic system have been extensively characterized and reported to be nearly ubiquitous, clonal mosaicism (CM) has more recently also been described across multiple solid tissues. However, outstanding questions remain about the parameters and processes of human somatic evolution in non-cancerous solid human tissues, including when clones arise, how they evolve over time, and what mechanisms lead to their expansion. Questions of timing and clonal dynamics can be addressed through phylogenetic reconstruction, which serves as a 'temporal microscope', while uncovering the mechanisms of expansion necessitates simultaneous phenotypic profiling. To address this gap, here we develop Single-cell Miniaturized Automated Reverse Transcription and Primary Template-directed Amplification (SMART-PTA) for joint single-cell whole-genome and whole-transcriptome sequencing for large scale and cost efficient interrogation of solid tissue CM. We established a workflow that generates hundreds of matched single-cell whole genome and transcriptome libraries within a week. We profiled phenotypically normal esophagus tissue from four aged donors and used somatic variants to build high-resolution single-cell lineages from >2,700 cells with accompanying transcriptomic information, reconstructing >70 years of somatic evolution. T cell expansions identified from T cell receptor (TCR) sequences validated the clonal structure of the single-nucleotide variant (SNV)-based phylogenies and phylogenetic cross-correlation analysis showed that epithelial cells had higher degrees of shared ancestry by spatial location compared to immune cells. Mapping mutation signatures to the phylogenetic tree revealed the emergence of tobacco/alcohol exposure-related signatures later in life, consistent with the donors' exposure histories. We identified variants in driver genes that were previously reported in the phenotypically normal esophagus, detecting clonal expansions harboring mutations in genes including TP53 and FAT1 . We mapped the evolution of clones with both monoallelic as well as biallelic TP53 loss, including a clone associated with high expression of cell cycling genes and higher chromosome instability. Leveraging the matched transcriptome data, we uncovered cell type biases in mutant clones, with a higher proportion of TP53 or FAT1 -mutant cells in an earlier basal epithelial cell state compared to wild-type cells. We further observed copy-neutral loss of heterozygosity (CNLOH) events on chromosome 9q that spanned the NOTCH1 locus in up to ∼35% of epithelial cells. Mapping CNLOH events to the phylogenetic tree revealed a striking pattern in which CNLOH was separately acquired many times, reflecting convergent evolution. Cells with CNLOH events were biased towards the earlier basal epithelial state, suggestive of a selective advantage that leads to prevalent recurrence of chr9q CNLOH. Together, we demonstrate that SMART-PTA is an efficient, scalable approach for single-cell whole-genome and whole-transcriptome profiling to build phenotypically annotated single-cell phylogenies with enough throughput and power for application to normal tissue somatic evolution. Moreover, we reconstruct the evolutionary history of the esophageal epithelium at high scale and resolution, providing a window into the dynamics and processes that shape clonal expansions in phenotypically normal tissues throughout a lifespan.
    DOI:  https://doi.org/10.1101/2025.10.11.681805
  19. bioRxiv. 2025 Oct 13. pii: 2025.10.13.682122. [Epub ahead of print]
    Programmable conjugative CRISPR interference targeting genotoxin in the gut.
    Brian Hamp, Hania Timek, Chengyuan Fang, Zongqi Wang, Amber E Haley, Maria Jennings, Collins I Chimezie, Noah Hutchinson, Zhihong Dong, Shannon McCollum, Saleh Khawaled, Yatrik M Shah, Omer Yilmaz, Jiahe Li.
      Among microbially derived metabolites that influence host disease, colibactin garners increasing attention for its roles in the rising incidence of early-onset colorectal cancer. Produced by pks + Escherichia coli, colibactin is a potent genotoxin, yet no approved therapeutics directly suppress it. Here, we engineered a self-transmissible conjugative plasmid to deliver CRISPR interference (CRISPRi) into multiple pks+ strains. This system silences transcription of colibactin biosynthetic genes and abolishes pks + E. coli genotoxicity without the resistance mutations associated with wild-type Cas9-mediated bacterial inhibition. In mice, conjugation-mediated CRISPRi reduces DNA damage and pks + E. coli colonization while preserving commensal diversity. Importantly, the system also lowers tumorigenesis driven by pks + E. coli and outperforms a pharmacologic inhibitor in a mouse colorectal cancer model. Finally, we extend this platform to silence a second pathogenic metabolite, establishing a translational strategy to neutralize diverse microbial metabolites and expanding the toolkit for programmable live biotherapeutics in the gut.
    DOI:  https://doi.org/10.1101/2025.10.13.682122
  20. Br J Surg. 2025 Nov 29. pii: znaf244. [Epub ahead of print]112(12):
    Multiple primary tumours in early-onset colorectal cancer: deciphering the risk.
    Spanish Early-Onset Colorectal Cancer (SECOC) Consortium
      
    DOI:  https://doi.org/10.1093/bjs/znaf244
  21. Discov Oncol. 2025 Nov 23.
    Single-cell transcriptomic analysis reveals the heterogeneity and functional characteristics of macrophage subpopulations in colon cancer.
    Jiazheng Zhao, Baochun Wang, Xiao Li, Chunting Wei, Yi Min, Dayong Wang.
       BACKGROUND: Colon cancer remains one of the leading causes of cancer-related mortality globally. Tumor-associated macrophages (TAMs) are key contributors to tumor progression within the tumor microenvironment (TME). However, the role of secreted phosphoprotein 1 (SPP1), a critical regulator of macrophage-tumor interactions, in specific macrophage subsets in colon cancer remains unclear.
    METHODS: We performed single-cell RNA sequencing (scRNA-seq) on tumor and adjacent normal tissues from three colon cancer patients. A comprehensive analysis integrating pseudotime trajectory, transcription factor network, cell-cell communication, and in silico SPP1 knockout modeling was conducted to characterize macrophage heterogeneity and function.
    RESULTS: Five macrophage subtypes were identified. Among them, the Macrophages_SPP1 was significantly enriched in tumors and exhibited enhanced glycolytic metabolism, lysosomal activity, angiogenesis, and immunosuppression functions. This subtype showed increased interactions with fibroblasts, particularly via FTL-SCARA5 and FTH1-SCARA5 ligand-receptor pairs, implicating roles in stromal remodeling. In silico SPP1 knockout identified 93 stable responsive genes enriched in MHC class II-related and immune regulatory pathways, highlighting the role of SPP1 in shaping an immunosuppressive TME.
    CONCLUSIONS: The Macrophages_SPP1 subtype may contribute to colon cancer progression through metabolic reprogramming and stromal interactions, suggesting that SPP1 and the FTL-SCARA5 axis could represent potential therapeutic targets.
    Keywords:  Colon cancer; Macrophages; SPP1; ScTenifoldKnk; Tumor microenvironment; scRNA-seq
    DOI:  https://doi.org/10.1007/s12672-025-04002-z
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