bims-enbcad Biomed News
on Engineering biology for causal discovery
Issue of 2025–12–14
twelve papers selected by
Xiao Qin, University of Oxford
  1. The key role of cellular plasticity in the development of colorectal cancer.
  2. Immunoregulatory roles of post-translational modifications in colorectal cancer: mechanisms and therapeutic implications.
  3. Causal modelling of gene effects from regulators to programs to traits.
  4. Cracking the cancer microbiome.
  5. Liquid biopsy.
  6. Clonal cell states link gastroesophageal junction tissues with metaplasia and cancer.
  7. Potential Impact of Updated Bayesian Deduction in Medicine: Application to Colonoscopy Prioritization.
  8. Liquid biopsies across the cancer care continuum.
  9. A next-generation dual guide CRISPR system for genetic interaction library screening.
  10. Artificial intelligence agents for biology.
  11. Inferring cell differentiation maps from lineage tracing data.
  12. From bulk RNA sequencing to spatial transcriptomics: a comparative review of differential gene expression analysis methods.
  1. Transl Res. 2025 Dec 04. pii: S1931-5244(25)00116-1. [Epub ahead of print]
    The key role of cellular plasticity in the development of colorectal cancer.
    Lingqiao Lou, Yanghui Cao, Zhiyuan Ma, Bei Ji, Shuhui Liu, Kenichi Mizuno, Shuji Terai, Biguang Tuo, Taolang Li, Xuemei Liu.
      The development of colorectal cancer, which is a malignant tumor demonstrating high morbidity and mortality worldwide, involves complex molecular mechanisms and biological processes. Early-stage colorectal cancer patients do not exhibit obvious clinical symptoms; thus, they are often diagnosed with middle-stage to late-stage disease. The overall survival of advanced colorectal cancer patients with metastasis and treatment resistance is poor. Notably, tumor cell plasticity promotes tumorigenesis, metastasis, and therapeutic resistance, thus leading to the high incidence and mortality of colorectal cancer. In-depth studies of cellular plasticity are expected to lead to the identification of new therapeutic targets. In this review, we systematically summarize the role of cellular plasticity in colorectal cancer development and explore the regulatory mechanisms associated with cellular plasticity in colorectal cancer, with the aim of providing a theoretical basis for the development of innovative therapeutic strategies for this type of cancer.
    Keywords:  Cellular Plasticity; Colorectal Cancer; Regulatory Mechanism; Treatment; Tumorigenesis
    DOI:  https://doi.org/10.1016/j.trsl.2025.12.002
  2. Cell Mol Life Sci. 2025 Dec 08.
    Immunoregulatory roles of post-translational modifications in colorectal cancer: mechanisms and therapeutic implications.
    Xinyue Liang, Jinhong Yao, Wenbo Jiao, Xiaolin Li, Bo Yang, Hongqiong Fan.
      Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, with tumor immune evasion posing a major challenge to effective immunotherapy. Post-translational modifications (PTMs), including phosphorylation, ubiquitination, acetylation, methylation, and glycosylation, are critical regulators of protein function and stability, profoundly influencing tumor immunogenicity and the tumor immune microenvironment. This review comprehensively examines how PTMs modulate key immune processes in CRC, such as antigen presentation, immune cell infiltration, and immune checkpoint regulation. We discuss PTM-mediated mechanisms that shape T cell exhaustion, macrophage polarization, and immunosuppressive cytokine networks within the tumor microenvironment. Moreover, we highlight the impact of PTMs on therapeutic response and resistance to immune checkpoint blockade and adoptive cell therapies. Emphasis is placed on emerging PTM-targeted strategies to enhance antitumor immunity and overcome immunotherapy resistance. Finally, we explore advances in multi-omics technologies and proteomic profiling that promise to accelerate the identification of PTM biomarkers and novel therapeutic targets. By integrating mechanistic insights with translational perspectives, this review aims to provide a foundation for leveraging PTMs to optimize immunotherapeutic approaches in colorectal cancer.
    Keywords:  Immune checkpoint blockade; Macrophage polarization; Phosphorylation; T cell exhaustion; Ubiquitination
    DOI:  https://doi.org/10.1007/s00018-025-05992-3
  3. Nature. 2025 Dec 10.
    Causal modelling of gene effects from regulators to programs to traits.
    Mineto Ota, Jeffrey P Spence, Tony Zeng, Emma Dann, Nikhil Milind, Alexander Marson, Jonathan K Pritchard.
      Genetic association studies provide a unique tool for identifying candidate causal links from genes to human traits and diseases. However, it is challenging to determine the biological mechanisms underlying most associations, and we lack genome-scale approaches for inferring causal mechanistic pathways from genes to cellular functions to traits. Here we propose approaches to bridge this gap by combining quantitative estimates of gene-trait relationships from loss-of-function burden tests1 with gene-regulatory connections inferred from Perturb-seq experiments2 in relevant cell types. By combining these two forms of data, we aim to build causal graphs in which the directional associations of genes with a trait can be explained by their regulatory effects on biological programs or direct effects on the trait3. As a proof of concept, we constructed a causal graph of the gene-regulatory hierarchy that jointly controls three partially co-regulated blood traits. We propose that perturbation studies in trait-relevant cell types, coupled with gene-level effect sizes for traits, can bridge the gap between genetic association and biological mechanism.
    DOI:  https://doi.org/10.1038/s41586-025-09866-3
  4. Nat Methods. 2025 Dec;22(12): 2494
    Cracking the cancer microbiome.
    Madhura Mukhopadhyay.
      
    DOI:  https://doi.org/10.1038/s41592-025-02953-3
  5. Nat Biotechnol. 2025 Dec;43(12): 1929
    Liquid biopsy.
      
    DOI:  https://doi.org/10.1038/s41587-025-02940-1
  6. Nat Commun. 2025 Dec 08. 16(1): 10952
    Clonal cell states link gastroesophageal junction tissues with metaplasia and cancer.
    Rodrigo A Gier, Sydney A Bracht, Jiazhen Rong, Raúl A Reyes Hueros, Madison L Wahlsten, Christopher Cote, Maureen DeMarshall, Tatiana A Karakasheva, Alexandra Strauss Starling, Amanda B Muir, Gary W Falk, Nancy R Zhang, Sydney M Shaffer.
      Barrett's esophagus is a common type of metaplasia and a precursor of esophageal adenocarcinoma. However, the cell states and lineage connections underlying the origin, maintenance, and progression of Barrett's esophagus have not been resolved in humans. Here, we perform single-cell lineage tracing and transcriptional profiling of patient cells isolated from metaplastic and healthy tissue. Our analysis unexpectedly reveals evidence for lineages spanning squamous esophagus, gastric cardia, and transitional basal cells at the tissue junction. We also identify lineages connecting Barrett's esophagus to both esophageal and gastric tissues. Barrett's esophagus biopsies consist of multiple distinct clones, with lineages that contain all progenitor and differentiated cell types. We discover Barrett's esophagus cell types, including tuft, ciliated, and BEST4+ cells, which we validate through both lineage relationships and spatial transcriptomics. In contrast, the precancerous dysplastic lesions show expansion from a single molecularly aberrant Barrett's esophagus clone. Together, these findings provide a single-cell view of the cell dynamics of Barrett's esophagus, linking cell states along the disease trajectory, from its origin to cancer.
    DOI:  https://doi.org/10.1038/s41467-025-66302-w
  7. Cancers (Basel). 2025 Nov 29. pii: 3845. [Epub ahead of print]17(23):
    Potential Impact of Updated Bayesian Deduction in Medicine: Application to Colonoscopy Prioritization.
    Pierre Collet, Felipe Quezada-Diaz, Carla Taramasco.
      Background/Objectives: This study presents and explores the potential of Updated Bayesian Deduction (UBD) using colorectal cancer (CRC) detection and prioritisation as a case example. Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, and its prognosis strongly depends on early detection and timely treatment. In Chile, colonoscopy waiting lists for symptomatic patients in public hospitals can exceed one year, limiting access to early diagnosis and reducing survival rates. Traditional single-test screening strategies, such as a single faecal immunochemical test (FIT), often yield uncertain results, contributing to inefficiencies in resource allocation. Methods: We propose a deductive approach that integrates evidence from multiple sequential and independent FITs to dynamically update the posterior probability of CRC. A case study is analysed with this Updated Bayesian Deduction over a four-round FIT protocol to assess how this could improve risk stratification compared to standard symptoms-based screening. Results: Our mathematical model shows that over 85% of colonoscopies for symptomatic patients were not urgent. We then demonstrate that, if 4-FIT UBD were used to screen Chile's Metropolitan Region population, only 96 out of 100,000 people would require an urgent colonoscopy to detect the 19.6 out of 100,000 individuals with CRC in this region. Many countries cannot afford a colonoscopy-based population screening, such as what is performed in Germany. Performing 4x FITs + a very small number of colonoscopies would be much more affordable and would get more countries to adopt general CRC screening. Conclusions: In countries with limited colonoscopy availability, such as Chile, where symptomatic patients can wait over a year for treatment in public hospitals, implementing a UBD-based strategy could drastically reduce costs and optimise the use of resources. This would improve access to colonoscopies for critical cases and ultimately enhance five-year survival rates. These findings highlight UBD as a promising approach for evidence-based precision medicine in CRC screening and prioritisation that is both explainable and adaptable.
    Keywords:  Evidence-Based Medicine; Resource Allocation; colorectal cancer screening; faecal immunochemical test; updated bayesian deduction
    DOI:  https://doi.org/10.3390/cancers17233845
  8. Nat Med. 2025 Dec 10.
    Liquid biopsies across the cancer care continuum.
    Blair V Landon, Akshaya V Annapragada, Noushin Niknafs, Victor E Velculescu, Valsamo Anagnostou.
      Liquid biopsies have the potential to transform precision oncology by enabling the sensitive and timely detection of cancer across various clinical settings. Minimally invasive analyses of circulating cell-free DNA (cfDNA) have emerged as cutting-edge approaches for cancer detection, characterization and monitoring. Early efforts focused on mutation-based targeted sequencing, whereas newer methods use whole-genome and epigenome sequencing combined with artificial intelligence to broaden the range of alterations that can be assessed in cfDNA. Despite these advances, substantial technical and clinical challenges prevent widespread adoption. Key areas for improvement include achieving clinically meaningful detection sensitivities, enhancing assay accessibility and prospectively evaluating the clinical sensitivity of circulating tumor DNA burden in early and metastatic settings, to support the integration of liquid biopsies into therapeutic decision-making. Here we discuss technologies and analytical methodologies in cfDNA detection, together with their clinical validity and utility. We highlight opportunities to address key challenges and to support the implementation of liquid biopsies throughout the cancer care continuum.
    DOI:  https://doi.org/10.1038/s41591-025-04093-9
  9. Nat Commun. 2025 Dec 06.
    A next-generation dual guide CRISPR system for genetic interaction library screening.
    Thomas Burgold, Emre Karakoc, Emanuel Gonçalves, Inigo Barrio-Hernandez, Lisa Dwane, Romina Silva, Emily Souster, Mamta Sharma, Alexandra Beck, Gene Ching Chiek Koh, Lykourgos-Panagiotis Zalmas, Mathew J Garnett, Andrew R Bassett.
      Pairwise perturbation of gene function using the CRISPR/Cas9 system has potential in screening for genetic interactions and synthetic lethal gene pairs to identify combination therapies for cancer. However, existing dual guide expression systems are cumbersome to clone, often result in a large proportion of undesired guide pairs and have an imbalance of guide expression from the two positions. Here, we demonstrate a next-generation system for dual guide delivery based around a tRNA spacer that allows a single-step cloning strategy, as little as 2% of undesired guide pairs, and highly balanced expression of the two guides. This system allows efficient library-scale screening for hundreds of thousands of genetic interactions using the well-understood Streptococcus pyogenes Cas9 (SpCas9) system. We use this to screen a 100,136 guide pair library in colorectal cancer cells and successfully identify synthetic lethal genetic interactions between paralogs or other known interacting genes, establishing our method for performing efficient large-scale genetic interaction screens. This system is versatile and could be used with most guide RNA vector systems, and for other uses of paired guide delivery, such as improving single gene knockout efficiency or improving guide detection in single cell or optical CRISPR screens.
    DOI:  https://doi.org/10.1038/s41467-025-67256-9
  10. Nat Methods. 2025 Dec;22(12): 2496-2497
    Artificial intelligence agents for biology.
    Lin Tang.
      
    DOI:  https://doi.org/10.1038/s41592-025-02958-y
  11. Nat Methods. 2025 Dec 08.
    Inferring cell differentiation maps from lineage tracing data.
    Palash Sashittal, Richard Y Zhang, Benjamin K Law, Henri Schmidt, Alexander Strzalkowski, Adriano Bolondi, Michelle M Chan, Benjamin J Raphael.
      During development, cells differentiate through a hierarchy of increasingly restricted cell types, a process that is summarized by a cell differentiation map. Recent technologies profile lineages and cell types at scale, but existing methods to infer cell differentiation maps from these data rely on heuristic models with restrictive assumptions about the developmental process. Here we introduce a quantitative framework to evaluate cell differentiation maps and develop an algorithm, called Carta, that infers an optimal differentiation map from single-cell lineage tracing data. The key insight in Carta is to balance the tradeoff between the complexity of the map and the number of unobserved cell type transitions on the lineage tree. We show that, in models of mammalian trunk development and mouse hematopoiesis, Carta identifies important features of development that are not revealed by other methods, including convergent differentiation of cell types, progenitor differentiation dynamics and new intermediate progenitors.
    DOI:  https://doi.org/10.1038/s41592-025-02903-z
  12. Hum Genomics. 2025 Dec 06.
    From bulk RNA sequencing to spatial transcriptomics: a comparative review of differential gene expression analysis methods.
    Maryam Kalantari-Dehaghi, Neda Ghohabi-Esfahani, Modjtaba Emadi-Baygi.
      
    Keywords:  Bulk RNA-seq; DEA; Direct RNA sequencing; Python; R; Spatial transcriptomics; scRNA-seq
    DOI:  https://doi.org/10.1186/s40246-025-00884-w
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