bims-enbcad Biomed News
on Engineering biology for causal discovery
Issue of 2025–11–09
nine papers selected by
Xiao Qin, University of Oxford
  1. Squidiff: predicting cellular development and responses to perturbations using a diffusion model.
  2. Epigenetically driven and early immune evasion in colorectal cancer evolution.
  3. Cellular senescence in precancer lesions and early-stage cancers.
  4. Site-specific DNA insertion into the human genome with engineered recombinases.
  5. Navigating the evolving landscape of colorectal cancer screening with a practical framework: a comprehensive analysis of existing and emerging technologies for informed decision-making.
  6. Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
  7. Early-Onset Colorectal Cancer in Transition-Evolving International Cancer Classifications and Incidence Patterns.
  8. Integrative Multi-Omics and Artificial Intelligence: A New Paradigm for Systems Biology.
  9. Circulating tumor cells: indicators of cancer progression, plasticity and utility for therapies.
  1. Nat Methods. 2025 Nov 03.
    Squidiff: predicting cellular development and responses to perturbations using a diffusion model.
    Siyu He, Yuefei Zhu, Daniel Naveed Tavakol, Haotian Ye, Yeh-Hsing Lao, Zixian Zhu, Cong Xu, Shradha Chauhan, Guy Garty, Raju Tomer, Gordana Vunjak-Novakovic, James Zou, Elham Azizi, Kam W Leong.
      Single-cell sequencing has revolutionized our understanding of cellular heterogeneity and responses to environmental stimuli. However, mapping transcriptomic changes across diverse cell types in response to various stimuli and elucidating underlying disease mechanisms remains challenging. Here we present Squidiff, a diffusion model-based generative framework that predicts transcriptomic changes across diverse cell types in response to environmental changes. We demonstrate the robustness of Squidiff across cell differentiation, gene perturbation and drug response prediction. Through continuous denoising and semantic feature integration, Squidiff learns transient cell states and predicts high-resolution transcriptomic landscapes over time and conditions. Furthermore, we applied Squidiff to model blood vessel organoid development and cellular responses to neutron irradiation and growth factors. Our results demonstrate that Squidiff enables in silico screening of molecular landscapes and cellular state transitions, facilitating rapid hypothesis generation and providing valuable insights into the regulatory principles of cell fate decisions.
    DOI:  https://doi.org/10.1038/s41592-025-02877-y
  2. Nat Genet. 2025 Nov 05.
    Epigenetically driven and early immune evasion in colorectal cancer evolution.
    Eszter Lakatos, Vinaya Gunasri, Luis Zapata, Jacob Househam, Timon Heide, Nicholas Trahearn, Ottilie Swinyard, Luis Cisneros, Claire Lynn, Maximilian Mossner, Chris Kimberley, Inmaculada Spiteri, George D Cresswell, Gerard Llibre-Palomar, Miriam Mitchison, Carlo C Maley, Marnix Jansen, Manuel Rodriguez-Justo, John Bridgewater, Ann-Marie Baker, Andrea Sottoriva, Trevor A Graham.
      Immune system control is a principal hurdle in cancer evolution. The temporal dynamics of immune evasion remain incompletely characterized, and how immune-mediated selection interrelates with epigenome alteration is unclear. Here we infer the genome- and epigenome-driven evolutionary dynamics of tumor-immune coevolution within primary colorectal cancers (CRCs). We utilize a multiregion multiomic dataset of matched genome, transcriptome and chromatin accessibility profiling from 495 single glands (from 29 CRCs) supplemented with high-resolution spatially resolved neoantigen sequencing data and multiplexed imaging of the tumor microenvironment from 82 microbiopsies within 11 CRCs. Somatic chromatin accessibility alterations contribute to accessibility loss of antigen-presenting genes and silencing of neoantigens. Immune escape and exclusion occur at the outset of CRC formation, and later intratumoral differences in immuno-editing are negligible or exclusive to sites of invasion. Collectively, immune evasion in CRC follows a 'Big Bang' evolutionary pattern, whereby it is acquired close to transformation and defines subsequent cancer-immune evolution.
    DOI:  https://doi.org/10.1038/s41588-025-02349-1
  3. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00447-7. [Epub ahead of print]
    Cellular senescence in precancer lesions and early-stage cancers.
    TBEL Consortium
      Cellular senescence plays dual roles in precancer lesions: initially serving as a tumor-suppressive barrier within the epithelial compartment and later contributing to a pro-tumoral precancer tissue microenvironment (PreTME) via a sustained, paracrine secretome known as senescent-associated secretory phenotype (SASP). This commentary highlights the role of senescence across various PreTME cell types, explores emerging pharmacologic and lifestyle interception strategies, and outlines current challenges for advancing biomarkers and clinical translation.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.006
  4. Nat Biotechnol. 2025 Nov 06.
    Site-specific DNA insertion into the human genome with engineered recombinases.
    Alison Fanton, Liam J Bartie, Juliana Q Martins, Vincent Q Tran, Laine Goudy, Courtney Kernick, Matthew G Durrant, Jingyi Wei, Zev Armour-Garb, April Pawluk, Silvana Konermann, Alexander Marson, Luke A Gilbert, Theodore L Roth, Patrick D Hsu.
      Insertions of large DNA sequences into the genome are broadly enabling for research and therapeutic applications. Large serine recombinases (LSRs) can mediate direct, site-specific genomic integration of multi-kilobase DNA sequences without a pre-installed landing pad, albeit with low insertion rates and high off-target activity. Here we present an engineering roadmap for jointly optimizing their DNA recombination efficiency and specificity. We combine directed evolution, structural analysis and computational models to rapidly identify additive mutational combinations. We further enhance performance through donor DNA optimization and dCas9 fusions, enabling simultaneous target and donor recruitment. Our top engineered LSR variants, superDn29-dCas9, goldDn29-dCas9 and hifiDn29-dCas9, achieve up to 53% integration efficiency and 97% genome-wide specificity at an endogenous human locus and effectively integrate large DNA cargoes up to 12 kb for stable expression in non-dividing cells, stem cells and primary human T cells. Rational engineering of DNA recombinases enables precise and efficient single-step genome insertion for diverse applications across gene and cell therapies.
    DOI:  https://doi.org/10.1038/s41587-025-02895-3
  5. Oncol Rev. 2025 ;19 1653617
    Navigating the evolving landscape of colorectal cancer screening with a practical framework: a comprehensive analysis of existing and emerging technologies for informed decision-making.
    Michael Sapienza, Cheryl Davis, Mathieu Boudes.
      The colorectal cancer (CRC) screening landscape has rapidly evolved, introducing new technologies alongside established methods. The lack of head-to-head observational studies comparing these diverse options impairs clinicians' and patients' ability to make informed choices in CRC screening test selection. This manuscript aims to provide a comprehensive review of existing and emerging CRC screening technologies and develop a practical framework for informed decision-making. We conducted a systematic review of current literature on CRC screening methods, including colonoscopy, fecal immunochemical test (FIT), multi-target stool DNA test (mt-sDNA), the next-generation multi-target stool DNA test, multi-target stool RNA test (mt-sRNA), and blood-based tests. We summarized performance characteristics, adherence rates, follow-up colonoscopy rates, accessibility, and costs for each method. Our review revealed significant variations in test performance, patient adherence, and implementation factors across screening modalities. Blood-based tests showed promise in terms of patient acceptance but currently have lower sensitivity for early-stage cancers with a higher participant adherence when screening navigation is provided. Our review led to the development of a comprehensive framework for evaluating CRC screening options, addressing the critical need for informed decision-making in this area. The framework encompasses five key dimensions: test performance (sensitivity and specificity for CRC and precancerous lesions), patient considerations (invasiveness, preparation, and location preferences), adherence and follow-up (real-world rates and diagnostic colonoscopy completion rates), accessibility and cost (insurance coverage, out-of-pocket expenses, and system integration), and screening interval (recommended frequency and long-term impact). By synthesizing data, the framework enables healthcare providers and patients to navigate the complex landscape of screening options, facilitating personalized recommendations tailored to individual risk factors, preferences, and healthcare system constraints. Future research should validate this framework in diverse clinical settings and update it as new technologies emerge, ensuring continued improvement in CRC screening participation, effectiveness, and outcomes.
    Keywords:  colorectal cancer; diagnosis; patients; prevention; screening
    DOI:  https://doi.org/10.3389/or.2025.1653617
  6. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00448-9. [Epub ahead of print]
    Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
    Eleanor Minogue, Pilar Baldominos, Lauren Hsu, Marcia C Haigis, Judith Agudo.
      The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.007
  7. JAMA Netw Open. 2025 Nov 03. 8(11): e2541741
    Early-Onset Colorectal Cancer in Transition-Evolving International Cancer Classifications and Incidence Patterns.
    Annalisa Trama, Laura Botta.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.41741
  8. OMICS. 2025 Nov 07.
    Integrative Multi-Omics and Artificial Intelligence: A New Paradigm for Systems Biology.
    Shashi Kant, Deepika, Saheli Roy.
      The increasing accessibility of high-throughput omics technologies has represented a paradigm change in systems biology, facilitating the systematic exploration of biological complexity at genomic, transcriptomic, proteomic, and metabolomic levels. Contemporary systems biology more and more depends on integrative multi-omics strategies to unravel the sophisticated, dynamic networks of cellular function and organismal phenotypes. Such methodologies enable scientists to clarify molecular interactions, decipher disease pathology, identify strong biomarkers, and guide precision medicine and synthetic biology initiatives. Recent technological breakthroughs in computational tools, ranging from early or late data integration, network analysis, and machine learning, have overcome obstacles of high-dimensionality, heterogeneity, and perturbations restricted to specific contexts. In this review, we critically assess the principles, methods, and applications of multi-omics integration, with an emphasis on cancer biology, microbial engineering, and synthetic biology. We showcase case studies in which integrative omics provided actionable findings. Finally, we address current limitations (e.g., data heterogeneity, interpretability) and forthcoming solutions (artificial intelligence, single-cell omics, cloud platforms). By closing the gap between molecular layers, multi-omics integration is moving toward predictive models of biological systems and revolutionary biotechnological applications.
    Keywords:  artificial intelligence; data integration; multi-omics; synthetic biology; systems biology
    DOI:  https://doi.org/10.1177/15578100251392371
  9. Pathol Oncol Res. 2025 ;31 1612181
    Circulating tumor cells: indicators of cancer progression, plasticity and utility for therapies.
    Tamás Richárd Linkner, Zsófia Brigitta Nagy, Alexandra Kalmár, Eszter Farkas, Fruzsina Bányai, Nikolett Szakállas, István Takács, Béla Molnár.
      Cancer is a deadly disease affecting millions of people worldwide. Circulating tumor cells (CTCs) represent a critical link between primary malignancies and metastasis, acting as key players in cancer dissemination, progression, and recurrence. Although rare, CTCs offer a valuable, non-invasive window into tumor biology and the evolution of disease in patients. CTCs can exist as single cells in the circulation, but some are shed and travel in larger groups, referred to as CTC clusters. These clusters possess a greater oncogenic potential compared to individual CTCs. In this review, we aim to provide insight into the dynamic biological processes underlying CTC generation, biology, and survival, with a focus on epithelial-to-mesenchymal transition (EMT) and beyond like cancer stem cells (CSCs), cellular plasticity, and senescence. A crucial aspect of CTC biology is EMT, a process that imparts cancer cells with increased motility, invasiveness, resistance to apoptosis, and the ability to intravasate and evade the immune system. Beyond EMT the cancer cells show further plasticity, allowing epithelial tumor cells to adopt mesenchymal or hybrid phenotypes, which enables adaptation to a changing microenvironment and enhances therapy resistance. Moreover, a subset of cancer cells can acquire stem cell-like properties, including self-renewal and tumor-initiating capacity. EMT, along with processes such as dedifferentiation, contributes to the generation of cancer stem cells. In recent years, studies have also highlighted the complex and paradoxical role of senescence in CTC biology. While senescence typically results in permanent cell cycle arrest, in cancer cells it may be reversible and can promote tumor cell dormancy, immune evasion, and metastatic reactivation. By exploring the connections between CTCs, EMT, CSCs, plasticity, and senescence, we aim to shed light on the unique biology of CTCs, their metastatic potential, and their contributions to tumor heterogeneity. We hope that a better understanding of these processes will help advance the development of novel biomarkers and therapeutic targets for solid tumors beyond EMT.
    Keywords:  EMT; cancer; circulating tumor cells; liquid biopsy; senescence
    DOI:  https://doi.org/10.3389/pore.2025.1612181
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