bims-enbcad Biomed News
on Engineering biology for causal discovery
Issue of 2025–12–07
fifteen papers selected by
Xiao Qin, University of Oxford
  1. Gut Check: Lactobacillus johnsonii Harnesses Bile Acids and Reactive Oxygen Species to Suppress High-Fat Diet-Induced Colorectal Cancer.
  2. Letter to Editor: Comparative analysis of artificial intelligence tools for the dissemination of colorectal cancer screening guidelines: a novel perspective on early screening education.
  3. Differential analysis of microbial profiles in colorectal cancer reveals modulations corresponding to immune subtypes.
  4. Decay of driver mutations shapes the landscape of intestinal transformation.
  5. Colorectal cancer stem cells crosstalk in tumor immune microenvironment and targeted therapeutic strategies.
  6. Biomechanical Phenotyping Reveals Unique Mechanobiological Signatures of Early-Onset Colorectal Cancer.
  7. Non-invasive colorectal cancer screening: emerging tools and clinical evidence.
  8. Precision Oncology: 2025 in Review.
  9. Hologenomic analysis of rectal mucus sampling for detection of adenomatous polyps and colorectal cancer.
  10. Non-invasive colorectal cancer screening methods: focusing on diagnostic genetic and epigenetic markers.
  11. A unified genetic perturbation language for human cellular programming.
  12. A guide to transcriptomic deconvolution in cancer.
  13. A human gut metagenome-assembled genome catalogue spanning 41 countries supports genome-scale metabolic models.
  14. A writing pact.
  15. Cellular characteristics of the immune microenvironment of colorectal cancer and progress in immunotherapy research.
  1. Cancer Res. 2025 Dec 01. 85(23): 4579-4581
    Gut Check: Lactobacillus johnsonii Harnesses Bile Acids and Reactive Oxygen Species to Suppress High-Fat Diet-Induced Colorectal Cancer.
    Prarthana J Dalal, Yatrik M Shah.
      Colorectal cancer is among the most prevalent and deadly malignancies worldwide, with its incidence being closely associated with lifestyle factors, including high-fat diets (HFD). Epidemiologic studies correlate HFD with increased colorectal cancer risk, yet individual susceptibility varies widely, and the underlying drivers remain poorly understood. Recent advances have shifted the paradigm from solely focusing on dietary composition to considering the contribution of host-microbe interactions and microbial metabolite profiles to interindividual differences in the risk of HFD-driven colorectal cancer. In this issue of Cancer Research, Liu and colleagues investigated Lactobacillus johnsonii as a protective bacterium that suppresses HFD-driven tumorigenesis. By promoting the conversion of conjugated bile acids to chenodeoxycholic acid, L. johnsonii triggers mitochondrial dysfunction, thus promoting the production of reactive oxygen species and inducing apoptosis to suppress colorectal cancer development. These preclinical findings provide mechanistic insight into the intersection of bile acid metabolism, gut microbiota, and carcinogenesis, and they lay the groundwork for future translational studies exploring probiotic-based cancer prevention approaches. See related article by Liu et al., p. 4600.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3546
  2. Int J Surg. 2025 Dec 05.
    Letter to Editor: Comparative analysis of artificial intelligence tools for the dissemination of colorectal cancer screening guidelines: a novel perspective on early screening education.
    Shiliang Ji, Yang Yang, Chen Zou.
      
    DOI:  https://doi.org/10.1097/JS9.0000000000004173
  3. Comput Biol Med. 2025 Dec 03. pii: S0010-4825(25)01700-7. [Epub ahead of print]200 111346
    Differential analysis of microbial profiles in colorectal cancer reveals modulations corresponding to immune subtypes.
    Sherlyn Jemimah, Amin F Majdalawieh, Mawieh Hamad, Amjad A Mahasneh.
      The proximity of the gut microbiome to the tumor microenvironment (TME) in colorectal cancer (CRC) presents a unique ecological niche. A systematic study of tumor-microbiome interactions will facilitate a deeper understanding of the heterogeneity in immune response and clinical outcomes in CRC. Previous studies have identified specific microbial species such as Fusobacterium nucleatum, pks+ Escherichia coli, and enterotoxigenic Bacteroides fragilis as contributors to CRC initiation and progression. However, the extent to which interactions between the microbiome and immune landscape affect prognosis and tumor heterogeneity remains poorly understood. To address this, immune subtypes from The Cancer Genome Atlas (TCGA) were integrated with microbial profiles from The Cancer Microbiome Atlas (TCMA) to examine the relationship between immune subtypes and the tumor microbiome in CRC. A cohort of 631 TCGA CRC cases with clinical, microbial and immune subtype data was analyzed. Differential abundance analysis indicated significant associations between specific taxa and immune subtypes. We demonstrate that pathogenic genera such as Selenomonas, Butyricimonas and Centipeda are significantly enriched (padjusted < 0.05) in the C2 IFN-ɣ dominant subtype. Our findings show that the abundance of pathogenic genera may play a critical role in driving the paradoxically poorer survival observed in CRC patients with the C2 subtype.
    Keywords:  Colorectal cancer; Host-microbe interactions; Immune landscape; Survival; Tumor microbiome
    DOI:  https://doi.org/10.1016/j.compbiomed.2025.111346
  4. 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
  5. 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
  6. Adv Sci (Weinh). 2025 Dec 01. e14693
    Biomechanical Phenotyping Reveals Unique Mechanobiological Signatures of Early-Onset Colorectal Cancer.
    Nicole C Huning, Munir H Buhaya, Victor V Nguyen, Afeefah Khazi-Syed, Haider A Ali, Adil Khan, Angela Fan, Robert C Fisher, Zhikai Chi, Indu Raman, Guangchun Chen, Chengsong Zhu, Mengxi Yu, Andrew R Jamieson, Sara Roccabianca, Victor D Varner, Cheryl M Lewis, Emina H Huang, Jacopo Ferruzzi.
      While both incidence and mortality of sporadic average-onset colorectal cancer (AO CRC, above 50 years of age) are in constant decline, sporadic early-onset colorectal cancer (EO CRC, under 50 years of age) is rising rapidly. Yet, the causes behind this rise remain poorly understood. Epidemiological studies indicate that lifestyle and environmental exposures may result in chronic inflammation, which is known to trigger tissue fibrosis. This study tests the hypothesis that fibrotic remodeling and biomechanical stiffening of colorectal tissues represent measurable hallmarks and potential drivers of EO CRC. Using primary human tissues, this work shows that EO CRC is associated with changes in collagen microstructure, increased stiffness, and elevated viscosity of primary tumors. Spatial transcriptional profiling and immunostaining reveal pro-fibrotic signatures in stromal cells, alongside enhanced Yes-associated protein (YAP) mechanotransduction and proliferation in epithelial cells of EO CRC tissues. Mechanistically, increasing matrix stiffness in vitro promotes proliferation of epithelial cells in 2D and 3D colorectal cancer models. Together, these findings establish EO CRC as a disease marked by early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation.
    Keywords:  YAP mechanotransduction; average‐onset; biomechanics; colorectal cancer; early‐onset; fibrosis; stiffness
    DOI:  https://doi.org/10.1002/advs.202514693
  7. Clin Endosc. 2025 Dec 03.
    Non-invasive colorectal cancer screening: emerging tools and clinical evidence.
    Hyoung Il Choi, Jae Myung Cha.
      The fecal immunochemical test (FIT) is a widely used non-invasive screening method for colorectal cancer (CRC) in many countries, valued for its simplicity, affordability, and reasonable sensitivity. Typically recommended on an annual or biennial basis, the FIT is effective in reducing CRC incidence and mortality by facilitating early detection. Stool DNA tests, including multitarget DNA tests and DNA methylation assays, demonstrate higher sensitivity than FIT for CRC and advanced adenomas, although they have slightly lower specificity and higher cost. These tests are generally performed at longer intervals, such as every 3 years, and are useful alternatives for individuals who are unwilling or unable to undergo a colonoscopy. Emerging non-invasive CRC screening tools, such as liquid biopsy, microRNA, microbiome tests, and urine-based tests, are being developed to improve patient compliance and test convenience. In particular, liquid biopsy offers a minimally invasive option that may be more acceptable to populations hesitant to undergo stool-based tests. Furthermore, the integration of machine learning with metagenomic sequencing data has shown promise in distinguishing patients with CRC from healthy individuals. As CRC screening evolves, these novel approaches may enable the development of more personalized, accessible, and effective screening strategies, ultimately improving adherence and reducing CRC-related mortality.
    Keywords:  Colorectal neoplasms; Fecal occult blood test; Liquid biopsy; Mass screening; Stool DNA
    DOI:  https://doi.org/10.5946/ce.2025.246
  8. Cancer Discov. 2025 Dec 02. 15(12): 2414-2421
    Precision Oncology: 2025 in Review.
    Nicholas Mai, Nicole Fernandez, Alexander Drilon, Debyani Chakravarty.
      This article discusses the specific advances made in precision oncology in 2025, in which we saw the approval of multiple new indications for known precision oncology agents and early promising data for novel agents that target either classical pathways or previously so-called undruggable targets. Additionally, we observed the continued development of antibody-drug conjugates and proteolysis-targeting chimeras, the advent of multiple blood-based methodologies for the early detection of cancer, the identification of nontraditional precision oncology biomarkers, and the growing presence of artificial intelligence technologies to generate precision oncology insights.
    DOI:  https://doi.org/10.1158/2159-8290.CD-25-1784
  9. Nat Commun. 2025 Dec 04. 16(1): 10876
    Hologenomic analysis of rectal mucus sampling for detection of adenomatous polyps and colorectal cancer.
    Andrew J Tock, Kamrun S Patel, Emma Morales-Walker, Linglan Zhang, Chris Orthodoxou, Alasdair D MacRitchie, Stephen Njoroge, Oladapo E Olaniru, Guy Mozolowski, Inês Mendes, Dave J Baker, Malvin Siew, Hannah N Humphrey, Eleanor T Walker-Davies, Frank McDermott, Sue Spencer, Susan Bird, Katerina-Vanessa Savva, Christopher Cunningham, Hannah Rottenburg, Heena Sisodia, Nick J Battersby, Gareth A R Jones, Jon Lacy-Colson, Alice E Baggaley, Christopher J Peters, Andrew Dodd, Kiran Kang, Chris Hamon, Ana Crespillo-Casado, Erica Law, Megan Sands, Hugo Lywood, Andrew J Page, Ian Daniels, Daniel Wise.
      Colorectal cancer (CRC) is the fourth most common cancer and the third leading cause of cancer-related mortality worldwide, with incidence rising among younger populations. The significant clinical and economic burden highlights the need for minimally invasive technologies capable of detecting pre-malignant and early-stage disease. Although liquid biopsy approaches have advanced, they have not achieved sufficient performance for clinical adoption when compared with colonoscopy, the current diagnostic gold standard. CRC is a mucosal pathology, yet current diagnostic methods have not leveraged mucosal biology. Here we demonstrate the clinical utility of rectal mucus specimens, collected using a minimally invasive device in an outpatient setting, without bowel preparation. Through a hologenomic approach integrating host and microbial genomics, we identify genetic and epigenetic aberrations and perturbations in microbial communities that drive the detection of adenomatous polyps and CRC in rectal mucus. Hologenomic integration enables superior stratification of CRC by disease site and stage compared with single-omics methods. In summary, we demonstrate the clinical utility of rectal mucus sampling combined with hologenomic analysis as a translatable prospective tool for diagnostic application.
    DOI:  https://doi.org/10.1038/s41467-025-66006-1
  10. 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
  11. 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
  12. 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
  13. Nat Microbiol. 2025 Dec 04.
    A human gut metagenome-assembled genome catalogue spanning 41 countries supports genome-scale metabolic models.
    Junyeong Ma, Nayeon Kim, Jun Hyung Cha, Wonjong Kim, Chan Yeong Kim, Yong-Ho Lee, Han Sang Kim, Yoon Dae Han, Dongeun Yong, Eugene Han, Sunmo Yang, Samuel Beck, Insuk Lee.
      Understanding the human gut microbiome requires comprehensive genomic catalogues, yet many lack geographic diversity and contain medium-quality metagenome-assembled genomes (MAGs) missing up to 50% of genomic regions, potentially distorting functional insights. Here we describe an enhanced Human Reference Gut Microbiome (HRGM2) resource, a catalogue of near-complete MAGs (≥90% completeness, ≤5% contamination) and isolate genomes. HRGM2 comprises 155,211 non-redundant near-complete genomes from 4,824 prokaryotic species across 41 countries, representing a 66% increase in genome count and a 50% boost in species diversity compared to the Unified Human Gastrointestinal Genome catalogue. It enabled improved DNA-based species profiling, resolution of strain heterogeneity and survey of the human gut resistome. The exclusive use of these genomes improved metabolic capacity assessment, enabling high-confidence, automated genome-scale metabolic models of the entire microbiota and revealing disease-associated microbial metabolic interactions. This resource will facilitate reliable functional insights into gut microbiomes.
    DOI:  https://doi.org/10.1038/s41564-025-02206-1
  14. Science. 2025 Dec 04. 390(6777): 1074
    A writing pact.
    Arjav Shah.
      
    DOI:  https://doi.org/10.1126/science.aee2617
  15. 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
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